Methodology and applicability of the human contact burn injury model: A systematic review

Anders Deichmann Springborg; Caitlin Rae Wessel; Lars Peter Kloster Andersen; Mads Utke Werner

doi:10.1371/journal.pone.0254790

. 2021 Jul 30;16(7):e0254790. doi: 10.1371/journal.pone.0254790

Methodology and applicability of the human contact burn injury model: A systematic review

Anders Deichmann Springborg ^1,^*, Caitlin Rae Wessel ², Lars Peter Kloster Andersen ³, Mads Utke Werner ^1,⁴

Editor: John Kramer⁵

PMCID: PMC8323928 PMID: 34329326

Abstract

The contact burn injury model is an experimental contact thermode-based physiological pain model primarily applied in research of drug efficacy in humans. The employment of the contact burn injury model across studies has been inconsistent regarding essential methodological variables, challenging the validity of the model. This systematic review analyzes methodologies, outcomes, and research applications of the contact burn injury model. Based on these results, we propose an improved contact burn injury testing paradigm. A literature search was conducted (15-JUL-2020) using PubMed, EMBASE, Web of Science, and Google Scholar. Sixty-four studies were included. The contact burn injury model induced consistent levels of primary and secondary hyperalgesia. However, the analyses revealed variations in the methodology of the contact burn injury heating paradigm and the post-burn application of test stimuli. The contact burn injury model had limited testing sensitivity in demonstrating analgesic efficacy. There was a weak correlation between experimental and clinical pain intensity variables. The data analysis was limited by the methodological heterogenicity of the different studies and a high risk of bias across the studies. In conclusion, although the contact burn injury model provides robust hyperalgesia, it has limited efficacy in testing analgesic drug response. Recommendations for future use of the model are being provided, but further research is needed to improve the sensitivity of the contact burn injury method. The protocol for this review has been published in PROSPERO (ID: CRD42019133734).

Introduction

Human experimental pain models are pivotal research tools in studying mechanisms of pain pathophysiology and pharmacodynamics of analgesics [1–64] (Fig 1). While animal models are principal in understanding the basic circuitry of nociceptive pathways as well as fundamental drug effects, human models evaluating sensory-discriminative and cognitive-evaluative aspects of pain are essential in pre-clinical research [65–67].

Experimental inflammatory pain models mimic the sensitization of primary afferent nociceptors and spinal processing seen in clinical pain [69], thus leading to primary hyperalgesia in the inflamed tissues and secondary hyperalgesia in the circumscribed ‘normal/undamaged’ tissues. A number of standardized inflammatory models evoking hyperalgesia are applied in experimental pain research, including the contact burn injury (CBI) model [33], the heat/capsaicin model [70], and the ultraviolet B (UVB) model [71].

The CBI-model involves tonic heating of the skin by a contact thermode inducing a first-degree burn injury. Critical factors that govern cutaneous burn injury depth are exposure temperature and exposure time, a relationship first proposed by Moritz and Henriques in 1947 [72]. In their hallmark experimental study, porcine and human skin was exposed to a contact thermode with varying exposure temperatures and times in order to establish a time-temperature graph. The generated graph indicated the lowest exposure time at a given temperature, causing microscopically verified epidermal cell death (Fig 2). Within the range of 44°C to 51°C, an increase in heating of 1°C meant that the exposure time required for the development of epidermal cell death was reduced by 50%. At 44°C, an exposure time of 6 h was required to induce epidermal cell death; thus, the authors concluded that, below this temperature, cellular reparative processes were able to prevent burn injury damage [72]. Further studies have confirmed that heating the skin at 45°C for 300 s only induces transient hyperalgesia [5,70,73].

Fig 2 — Double-logarithmic time-temperature relationship of the burn injury (left panel) and inclusion criteria for minimum exposure temperature and exposure time (right panel). The grey line represents a regression plot with 95% confidence bands (dashed red lines) on the logarithmic relationship between exposure temperature (X) and exposure time (Y) in producing a burn injury (modified from Naert et al. [27] based on data from Moritz and Henriques [72]; Y = -28.3*X + 116.4, R² = 0.98). The open circles represent the longest exposure time at a given temperature that failed to destroy the epidermis but induced a hyperemic skin response in humans. The red line is a parallel shift of the regression line through the heating paradigm of 300 s at 45°C (Y = -28.3*X + 113.4), serving as a ‘safety margin’ and inclusion criteria in this review (see right panel for specific values). The solid grey circles represent the heating paradigms of the included studies. The minimum exposure time at a given temperature that meets the inclusion criteria is outlined in the table (right panel, corresponding to the parallel shifted red line).

The application of the CBI-model generally involves the CBI as a conditioning stimulus with pain intensity ratings during the induction followed by Quantitative Sensory Testing, i.e., a standardized activation of the sensory system by application of graded chemical, electrical, mechanical, or thermal stimuli, with an assessment of the evoked psychophysical responses [74]. However, the employment of the CBI-model across studies generally lacks consensus regarding essential methodological variables such as exposure time, heating temperature, and contact thermode surface area. These inconsistencies present major confounding factors that may influence outcome assessments and thus impose a challenge to the general validity of the model.

The primary aim of the present study is to systematically and critically review the methodologies and outcomes of experimental human CBI-studies. The secondary aim is to propose a uniform, applicable CBI-paradigm based on a discussion of the limitations and advantages of the current studies.

Materials and methods

A protocol is available at PROSPERO (https://www.crd.york.ac.uk/prospero/) with ID CRD42019133734. The PRISMA checklist is available as supporting information (S1 Checklist).

Eligibility criteria

Following criteria were used to retrieve relevant articles:

Experimental studies applying a CBI-method in humans were considered.
Only studies that met the exposure temperature and exposure time criteria outlined in Fig 2 were included. The graph accommodates a parallel shift of the double-logarithmic graph original by Moritz and Henriques in order to fit the heating paradigm of 45°C for 300 s [27,72].
Studies applying a tonic heat stimulus (duration ≥ 1 min) with identical heating paradigms between subjects were included.
Studies applying phasic heat stimuli (stimulus duration < 1 min, or a compound burst of stimuli) were excluded.
Studies applying radiant heat, e.g., CO₂-laser, as a conditioning stimulus, were excluded.
Studies applying additional conditioning stimuli to the burn injury area, thereby increasing the hyperalgesic response (e.g., heat/capsaicin model), were excluded.
Research articles published before 1992 were not considered relevant for this review and were thus excluded.
Non-English studies, conference abstracts, material from textbooks, and review articles were not included.

Search strategy and selection

A literature search was conducted in PubMed, Web of Science, and EMBASE (final search conducted 15-JUL-2020) using the following search criteria: (hyperalgesia OR pain threshold OR detection threshold OR pain sensitization OR pain measurement OR temporal summation) AND (contact heat stimulation OR heat injury OR burn injury OR local hyperthermia OR thermode) AND (healthy subjects OR healthy volunteers OR human subjects OR humans OR man OR patients). The search criteria were modified for EMBASE to fit the index terms in this database (S1 File). Google Scholar was used for forward citation chaining of all included articles after the initial reference search. The reference-lists from eligible articles were examined for additional relevant articles as well. No attempt to contact study authors for additional unpublished material was made. The authors (ADS, CRW) individually screened all identified articles based on title and abstract. In the case of disagreement between the authors regarding the relevance of an article, the final decision was made by the senior author (MUW). Subsequently, the relevant articles underwent full-text screening to determine final eligibility.

Categorization of studies

The studies were separated into the following categories:

Intervention studies were characterized by the evaluation of the CBI-model in terms of both pharmacodynamic and non-pharmacodynamic interventions in reducing the hyperalgesic and/or inflammatory response of the CBI.
Non-intervention studies were characterized by the application of the CBI-model in all other research areas than evaluation of analgesic efficacy

The non-intervention studies were further subdivided into the following categories:

2.1
Methodological studies were characterized by the evaluation of the CBI-model in terms of validity, reproducibility, and comparison to other models of hyperalgesia.
2.2
Physiological studies were characterized by the evaluation of the CBI-model in terms of physiological mechanisms, including evaluation of imaging, pain heritability, inflammatory mediators, the contribution of the endogenous opioid system, characterization of the secondary hyperalgesia are (SHA), temporal summation, and the contribution of different receptors in the hyperalgesic response.
2.3
Predictive studies were characterized by the evaluation of the CBI-model in terms of predicting pain, primarily following surgery.
2.4
Miscellaneous studies included all CBI-studies that could not be classified into any of the previously described categories (see S2 File for data regarding these studies).

Data extraction and data analysis

Data were extracted from relevant articles using a standardized data extraction sheet including the following information: general article information, aim, design of the study, study timeline, description of participants, description of the burn injury and additional injuries, interventions, outcome measures, post-CBI changes for each outcome, the effect of interventions on outcomes, key conclusions of the study, and study limitations. Methodological quality was assessed using the Oxford Quality Scoring System [75] for all intervention studies. This system evaluates information about randomization, blinding, and withdrawals, and drop-outs. Each study is scored on an ordinal scale of 0–5, with 0–2 representing a low-quality score and 3–5 representing a high-quality score. Before commencing data extraction for each article, the authors (ADS, CRW) individually extracted data from the same article and compared data sheets to ensure uniform and consistent data extraction. Data were synthesized into tables and analyzed qualitatively. Data are reported as median (interquartile range) unless stated otherwise.

Results

Literature search

A PRISMA flow diagram illustrating the number of retrieved records is presented in Fig 1. The final search resulted in 4,206 records. After the exclusion of 879 duplicates, a total of 3,327 records were analyzed. Through title and abstract review, 3,254 records were excluded. The remaining 73 records were assessed for eligibility, and 14 of these were excluded [76–89]. Five studies were additionally retrieved from reference lists and citation chaining, yielding a total of 64 studies relevant for this review [1–64]. Before commencing the literature search, the authors searched for similar reviews in the field of contact burn injuries on PubMed and PROSPERO. We found one published review from 2016 regarding the pharmacological sensitivity of the CBI model [67]. This study did not focus on methodological aspects of the CBI model in detail.

Contact burn injury characteristics

CBI-characteristics for each study are presented in Table 1.

Table 1. Contact burn injury characteristics.

First author	Heat paradigm	Contact area (cm²)/manufacturer	Contact thermode pressure (kPa)	Induction site	Adverse effects	Pain rating	Sensory testing	Post-CBI changes
Intervention
Dahl J [7]	CTRL: 420 s at 50°C I: 360 s at 50°C	3.75/Somedic	26	Calf	Blistering 4-8h post-injury (100%)	NR	CTRL: PI, 40´, 70´, 100´, 130´, 160´, 190´ I: PI^¤, 40´, 70´, 100´, 130´, 160´, 190´^†	↑90WDT_in, ↓WDT_out^††, ↓HPT_in, P-SHA^, B-SHA^, ↓Flare^†††, →HPT_out
Møiniche S [22]	360 s at 49°C	3.75/Somedic	NR	Calf	Blistering (n NR)	NR	24h, 72h, 168h, 14 days	↑Flare, ↑Blistering
Møiniche S [25]	300 s at 49°C	3.75/Somedic	NR	Calf	Blistering (n NR)	NR	PI^¤, 30´^¤, 60´, 120´, 180´, 240´, 300´, 360´	↓HPT, ↓PPT
Møiniche S [24]	240 s at 49°C	3.75/Somedic	NR	Calf	Blistering (n NR)	NR	-90´^¤, -5´, 2h, 4h, 6h	↓HPT, ↓HPTo, P-SHA^*, ↓MPT, ↑EI
Brennum J [5]	420 s at 47°C	12.5/Somedic	8	Calf	No	NR	-30´^¤, 150´, 330´, 390´ (+CBI at 180´)	↓HPT, ↓HPTo, P-SHA^, B-SHA^, →WDT, →Flare, →ST
Møiniche S [26]	300 s at 49°C	3.75/Somedic	NR	Calf	Blistering (n NR)	NR	-1.5h^¤, -5´, 3h, 6h, 12h, 24h	↓HPT, ↓HPTo, ↑P-SHA, ↓MPT, ↑EI
Pedersen JL [35]	300 s at 49°C	3.75/Somedic	NR	Calf	Blistering (n NR)	NR	-1h^¤, -5´, 3h, 24h, 48h, 72h	↓HPT, ↓HPTo, P-SHA^*, ↓MPT, ↑EI
Ilkjær S [13]	420 s at 47°C	12.5/Somedic	8	Calf	No	eVAS	PI^¤, -5´, 40´, 110´, 180´	↓HPT, P-SHA^, B-SHA^
Lundell JC [17]	100 s at 50°C	1/MIF	NR	Forearm	No	Magnitude estimation	~-90´^¤, ~-50´, ~10´	↓HPT, ↑H-pain
Pedersen JL [30]	300 s at 49°C	3.75/Somedic	4.5	Calf	Blistering (n NR)	NR	PI^¤, 16h, 20h, 24h, 48h	HPT?, P-SHA^*, MPT?, EI?, ↑Blistering
Pedersen JL [31]	300 s at 49°C	3.75/Somedic	4.5	Calf	Blistering (n NR)	Verbal rank score (0–100)	PI^¤, 1h, 4h, 6h, 8h, 10h, 12h	P-SHA^*, MPT?, EI?, ↑Blistering
Warncke T [52]	300 s at 47°C	12.5/Somedic	8	Calf	No	NR	B₁: PI^¤, 90´, 150´, 210´, 270´ B₂: PI^¤, -10´, 30´, 60´, 90´	B₁: ↓HPT, ↑P-SHA, ↓HPTo B₂: ↓HPT, P-SHA^*, ↓HPTo
Ilkjær S [12]	420 s at 47°C	12.5/Somedic	8	Calf	No	eVAS	PI^¤, -15´, 1h, 2h	↓HPT, P-SHA^, B-SHA^
Pedersen JL [36]	420 s at 47°C	12.5/Somedic	NR	Calf	Blistering (n NR)	VAS	PI^¤, PI, 1h, 2h, 4h, 6h	↑EI, P-SHA^, B-SHA^?, MPT?, HPT?, H-pain?, ST?
Petersen KL [39]	420 s at 47°C	12.5/Somedic	8	Calf	Blistering (n = 8)	eVAS	1h, 2h, 3h	P-SHA^, B-SHA^, B-pain_out^*
Warncke T [53]	420 s at 47°C	12.5/Somedic	8	Calf	NR	NR	PI^¤, -10´, 30´, 90´, 150´	↓HPT_in, ↓MPT_in, P-SHA^*, TS_M,out^§§§§, →TDT_in, HPT_out?, WDT_in/out?, TDT_out?, MPT_out?, ST?
Warncke T [54]	360 s at 47°C	12.5/Somedic	8	Calf	No	NR	-10´^¤, 30´^¤, 65´, 95´, 125´	↓HPT_in, ↓MPT, ↑P-SHA, ↑B-SHA, ↑TS_M,out, ↑ST, →WDT, →\|CDT\|, →CPT, →TDT, →HPT_out
Pedersen JL [32]	420 s at 47°C	12.5/Somedic	4.5	Calf	Blistering (20%), skin discoloration for 3 weeks (25%)	VAS	-70´^¤, -40´, 0´, 60´, 120´	↑WDT, ↓HPT, ↑H-pain, ↑P-SHA, ↓MPT, ↑M-pain_in, ↑M-pain_out, B-SHA^*
Hammer NA [10]	420 s at 47°C	12.5/Somedic	6.9	Calf	No	VAS	PI^¤, -15´, 0´, 1h, 2h, 3h	↓MPT, ↑M-pain_in/out, ↑P-SHA, ↓HPT, ↑H-pain_short, B-SHA?, H-pain_long?
Mikkelsen S [20]	420 s at 47°C	12.5/Somedic	NR	Calf	NR	NR	-5´^¤, 60´^¤, 90´, 135´	↓HPT, P-SHA^, B-SHA^
Sjölund KF [49]	420 s at 47°C	12.5/Somedic	NR	Calf	Minor blistering (n = 2)	NR	-15´^¤, 0´, 60´, 120´	↓HPT_in, ↓MPT_in/out, P-SHA^, B-SHA^, →\|CDT_in/out\|, →WDT_in/out, →HPT_out, →H-pain_in/out, →M-pain_in/out
Holthusen H [11]	300 s at 47°C^‡	4.5/Melcor	4.5	Forearm	No	eVAS	PI^¤, 0´, 30´, 60´, 90´, 120´, 180´, 240´, 24h	↓HPT, ↑P-SHA, ↓MPT, WDT?, TDT?
Lillesø J [16]	420 s at 47°C	12.5/Somedic	6.9	Calf	No	VAS	PI^¤, PI, 0´, 60´, 120´, 175´, 235´	↑WDT^‡‡, ↓HPT, ↑H-pain, ↑P-SHA^, B-SHA^, ↓MPT, ↑M-pain_in/out, →\|CDT\|
Mikkelsen S [21]	420 s at 47°C	12.5/Somedic	NR	Calf	NR	eVAS	-20´^¤, 20´, 80´, 140´, 200´, 260´	↓HPT, P-SHA^, B-SHA^
Warncke T [55]	420 s at 47°C	12.5/Somedic	8	Calf	No	NR	-30´^¤, 30´, 110´, 150´	↓HPT_in, ↓MPT_in/out, ↑TS_M,out, P-SHA^, B-SHA^, ↑ST_in^##, →ST_out, →WDT, →TDT, →HPT_out
Brennum J [6]	420 s at 47°C	12.5/Somedic	2.7	Calf	No	eVAS	-10´^¤, 60´^¤, 120´^¤, 180´, 240´	↓HPT, ↑H-pain_short, ↑H-pain_long, P-SHA^, B-SHA^
Werner MU [60]	420 s at 47°C	12.5/Somedic	5.5	Calf	Minor blistering (n = 3)	VAS	-180´^¤, -5´, 0´, 60´, 120´, 180´	↓HPT, ↓MPT, P-SHA^, B-SHA^, ↑M-pain_in/out, ↑WDT^‡‡, →\|CDT\|
Werner MU [58]	420 s at 47°C	12.5/Somedic	5.5	Calf	NR	VAS	-120´^¤, 60´, 120´, 180´, 240´	↑EI, P-SHA^, B-SHA^, ↓MPT, ↑M-pain, ↓HPT, ↑H-pain, →WDT, →\|CDT\|
Werner MU [59]	420 s at 47°C	12.5/Somedic	6.5	Calf	NR	VAS	-5´^¤, 55´, 85´, 125´, 165´, 205´	↓HPT, P-SHA^*, ↓MPT, ↑M-pain_in/out, ↑EI, ↑ST_in, →\|CDT\|, →WDT, ST_out?
Schulte H [47]	420 s at 46°C	12.5/Somedic	1.9	Calf	No	NR	-15´^¤, 15´^¤, 45´, 75´, 105´	P-SHA^*, ↓MPT_in/out, ↑TS_M,in, ↑TS_M,out TDT_in/out?
Schulte H [48]	420 s at 47°C	12.5/Somedic	NR	Forearm	No	NR	-55´^¤, 30´^¤, 155´, 275´	↓MPT_in/out, ↑TS_M,in, ↑TS_M,out, P-SHA^*
Robertson L [63]	120 s at 48°C	0.79/TC	1.3	Forearm	NR	NR	30´^¤, ~40´^¤, ~50´	↓HPT^#, ↑H-pain^#, ↑M-Pain^#
Stubhaug A [51]	300 s at 47°C	12.5/Somedic	8	Abdomen	No	eVAS	-45´^¤, 30´^¤, 60´, 105´, 165´	↓HPT, P-SHA^*
Ravn P [43]	420 s at 47°C	12.5/Somedic	NR	Calf	NR	VAS	PI^¤, 1h, 2h, 3h	→HPT, →\|CDT\|, P-SHA?, MPT?, WDT?
Andersen LPH [1]	420 s at 47°C	12.5/Somedic	NR	Calf	NR	VAS	-90´^¤, 60´, 120´, 240´, 360´	↓MPT_in/out, ↓HPT, ↑DT, ↑EI, ↑P-SHA, →WDT
Rasmussen VM [41]	420 s at 47°C	12.5/Somedic	NR	Calf	No	VAS	-15´^¤, 30´, 70´, 110´, 160´, 220´	↓HPT, ↓MPT, ↑EI, →\|CDT\|, →WDT, P-SHA?
Wahl AM [64]	420 s at 47°C	12.5/Somedic	NR	Calf	No	VAS	-20´^¤, 100´, 160´, 220´	↓HPT, ↓MPT, →\|CDT\|, →DT, ↑P-SHA, SE?, WDT?
Non-intervention
Methodological
Møiniche S [23]	300 s at 49°C	3.75/Somedic	26	Calf	Blistering (n NR)	NR	PI, 3h, 6h, 24h, 30h, 48h, 54h, 72h	↓HPT, ↓HPTo^¤¤¤¤, P-SHA^, B-SHA^, ↓MPT, ↑EI
Pedersen JL [33]	420 s at 47°C	12.5/Somedic	4.5	Calf	Blistering (20%), skin discoloration for 3 weeks (25%)	VAS	-105´, -30´, 0´, 1h, 2h, 4h, 6h	↑WDT^‡‡, ↓HPT, ↑H-pain, ↑\|CDT\|^‡‡‡, ↑P-SHA, B-SHA^*, ↓MPT, ↑EI
Yucel A [61]	420 s at 47°C	12.5/Somedic	4.5	Forearm	NR	eVAS	~-30´, 60´, ~70´, ~80´	P-SHA^, B-SHA^, SBF_in/out?, ST?, ↑Flare
Yucel A [62]	420 s at 47°C	12.5/NR	4.5	Forearm	No	eVAS	-5´, 60´	↓HPT-SS_out, ↓HPT-RS_out, P-SHA^, B-SHA^, ↑MI-Pain_in, ↑M-Pain_in/out, →TS_H,out, →TS_I,in, →MI-Pain_out, ↓EPT-SS_out, ↓EPT-RS_out, TS_E,out?, ↑TS_I,out, ↑TS_M,in/out, ↑Flare
Naert ALG [27]	420 s at 47°C	9/Medoc	NR	Thigh	NR	eVAS	Only QST before CBI^§§§	NA
Bishop T [4]	330 s at 45°C	10.24/Medoc	2.9	Forearm	No	NR	PI, 15´	↑P-SHA, ↑B-SHA, ↓MPT, ↑Flare, ↑SBF, →HPT
Ringsted TK [44]	420 s at 47°C	12.5/Somedic	NR	Calf	NR	VAS	45–75´^¶	P-SHA^*
Physiological
Pedersen JL [29]	420 s at 47°C	12.5/Somedic	4.5	Calf	Blistering (n NR)	VAS	PI, 0´, 1h, 2h, 4h	P-SHA^*, ↓MPT, ↓EPT-SS_in, →EPR_in/out, →TS_E,in/out, →EPT-SS_out
Pedersen JL [34]	420 s at 47°C	12.5/Somedic	4.5	Calf	Blistering (20%), skin discoloration for 3 weeks (25%)	VAS	-70´, -40´, 0´, 1h, 2h	↓HPT, ↑H-pain_in/out, ↑P-SHA, ↓MPT, ↑M-pain_in/out, B-SHA^*?
Schulte H [46] B	420 s at 47°C	12.5/Somedic	1.9	Calf	Minor blistering (n = 3)	NR	-10´, 5´, 15´, 30´, 45´, 60´	P-SHA^*, ↑Flare, ↑ST_in^§, ↑ST_out^§§, ↑SBF_area
Norbury TA [28]	330 s at 45°C	0.3/Medoc	2.7	Forearm	NR	NRS	PI, 15´	↓HPT, P-SHA^, B-SHA^, ↑Flare
Drummond PD [8]	120 s at 48°C	3.1/Custom-built	NR	Forearm	NR	NRS	PI, 30´^¶¶	↓HPT, ↑H-pain, EPS^*
Robertson L [45]	120 s at 48°C	0.8/TC	1.3	Hand	NR	NR	30´, ~35´, ~45´, ~50´	↓HPT^#, ↑ST^#
Drummond PD [9]	120 s at 48°C	3.1/Custom-built	NR	Forearm	No	NR	PI^¤, PI, ~30´, ~60´, ~85´	↓HPT, ↑H-pain
Kupers R [15]	420 s at 47°C	9/Medoc	NR	Thigh	NR	eVAS	Only QST before CBI	NA
Petersen LJ [40]	300 s at 49°C	3.75/Somedic	4.5	Calf	NR	NR	No QST	NA
Kupers R [14]	420 s at 47°C	9/Medoc	NR	Thigh	NR	eVAS	Only QST before CBI	NA
Pereira MP [38]	420 s at 47°C	12.5/Somedic	NR	Calf	Hyperpigmentation 23 days post-injury (n = 1)	VAS	PI, 1h, 2h, 3h^††††	↑P-SHA
Asghar MS and Pereira MP [2]	420 s at 47°C	Screening: 12.5/Somedic Experimental: 9/Medoc	NR	Calf	NR	NRS	S-day: PI, 0´ E-day: PI, 100´	P-SHA?, M-pain_in/out?
Pereira MP [37]	420 s at 47°C	12.5/Somedic	NR	Calf	NR	VAS	PI, 1h, 2h, 3h^‡‡‡‡	↓HPT, ↑P-SHA, B-SHA?, WDT?
Slimani H [50]	420 s at 47°C	12.5/Somedic	NR	Calf	No	eVAS	-10´, 60´, 24h	↓H-pain_AF,out^, ↓H-pain_CF,in^###, ↓H-pain_CF,out^, ↓HPT_AF,in^, ↑HPT_CF,in^####, ↑HPT_CF,out^####, P-SHA^, ↓RTFD_AF,in, →H-pain_AF,in, →RTFD_CF,in/out, →RTFD_AF,out, →HPT_AF,out
Predictive
C₁: Werner MU [57] C₂: Werner MU [56]	C₁/C₂: 420 s at 47°C	C₁/C₂: 12.5/Somedic	C₁/C₂: 6.5	C₁/C₂: Calf	C₁/C₂: NR	C₁/C₂: VAS	C₁: -5´, 60^´¶¶¶ C₂: -5, 60´	C₁/C₂: ↓HPT, ↑H-pain, P-SHA^*, ↓MPT, ↑M-pain
Ravn P [42]	420 s at 47°C	12.5/Somedic	NR	Calf	Blistering (n = 18)^¤¤	VAS	PI, 1h, 2h, 3h	↑WDT^¤¤¤, ↓HPT, ↑P-SHA^¶¶¶¶, ↓MPT_in/out, →\|CDT\|
Lunn TH [18]	420 s at 47°C	12.5/Somedic	NR	Thigh	No	eVAS	Only QST before CBI	NA
Miscellaneous
Matre D [19]	300 s at 46°C	12.5/Somedic	NR	Forearm	NR	eVAS	0´	P-SHA^, B-SHA^, MPT^, M-pain^
Aslaksen PM [3]	240 s at 46°C	9/Medoc	NR	Forearm	NR	VAS	No QST	NA

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AF = A-fibers; B-pain = motor brush-evoked pain ratings; B-SHA = brush secondary hyperalgesia area (allodynia); CBI = contact burn injury; CBI-pain = CBI-induced pain ratings; CDT = cool detection threshold; CF = C-fibers; CTRL = control; DT = dermal thickness; EI = erythema index; EPR = electrical pain response to a single stimulus; EPS = electrically-evoked pain sensations; EPT = electrical pain threshold; EPT-RS = electrical pain threshold repetitive stimuli; EPT-SS = electrical pain threshold single stimulus; eVAS = electronic visual analog scale; Flare = area of flare; H-pain = heat-evoked pain rating; HPT = heat pain threshold; HPTo = heat pain tolerance; I = intervention; M-pain = punctate mechanical-evoked pain rating; Md = median; MI-pain = mechanical impact-evoked pain ratings; MIF = Medical Instrumentation Facility of Yale University School of Medicine; MPT = mechanical pain threshold; NA = not applicable; NR = not reported; P-SHA = punctate secondary hyperalgesia area; PI = pre-burn injury; PPT = pressure pain threshold; PPTo = pressure pain tolerance; QST = quantitative sensory testing; RTFD = reaction time frequency distribution; SBF = skin blood flow; ST = skin temperature; TC = thermocouple-controlled cautery unit, purpose-built; TDT = tactile detection threshold; TS_M/TS_E/TS_I/TS_H = temporal summation to punctate mechanical/electrical/mechanical impact/heat stimulation; VAS = visual analog scale; WDT = warmth detection threshold.

* not assessed at baseline.

** significant at 24h post-CBI.

*** significant at 1h post-CBI for both sham and burn site, but only remained decreased in the burn group at 24h.

¤ pre-intervention assessment.

¤¤ due to malfunction.

¤¤¤ only significant at 1h post-CBI.

¤¤¤¤ only measured on one of the two experimental days.

# compared only to the control site.

## minor increase only on the first measurement at 30´ post-CBI on all experimental days.

### significant at 1h post-CBI, but no difference between sham and burn site.

#### significant only compared to baseline, similar for both sham and burn group.

† additional pre-intervention time-points before CBI on pre-injury block day and at 30´ post-CBI on post-injury block day.

†† only decreased on day 1 of control day, and not day 2.

††† developed in all subjects but none at 160´ post-CBI.

†††† additional assessment time-points at 72h post-CBI (pre-naloxone infusion) and 73h post-CBI (post-naloxone infusion).

‡ preliminary study with heat paradigm of 300 s at 49°C where burns resulted in second degree burns.

‡‡ significant only at 0´ post-CBI.

‡‡‡ significant only at 0´ post-CBI except in injury 2 where it was still present at 1h post-CBI.

‡‡‡‡ additional assessment time-points at 165h post-CBI (pre-naloxone infusion), and at 30´, 45´, and 60´ post-infusion.

§ back to baseline at 60´ post-CBI.

§§ back to baseline at 30´ post-CBI.

§§§ 12 subjects were retested after 3 months.

§§§§ not compared pre- to post-CBI, but temporal summation occurred in 8/10 subjects post-CBI.

¶ 2 observers, SHA assessments in two parts of 15 min each.

¶¶ burn injury day, assessment time-points were repeated for each of 3 sites.

¶¶¶ 6 days before and 1 day after surgery.

¶¶¶¶ no P-value reported, but 88/100 developed secondary hyperalgesia. Arrows indicate significant increases (↑) or decreases (↓), or no difference (→) post-CBI compared to pre-CBI; ‘?’ indicates that the post-CBI change was unclear. The Sensory testing column contains time-points of sensory testing in relation to the burn injury induction (time 0); negative values thus signify assessments pre-CBI, whereas positive values signify assessments post-CBI (including 0´ indicating immediately after the CBI); PI indicates an unspecified pre-burn injury time-point.

Contact burn injury methodology

Heating paradigm: The most common heating paradigm was 420 s at 47°C (40/64 [63%] studies; Fig 2) [1,2,5,6,10,12–16,18,20,21,27,29,32–34,36–39,41–44,46,48–50,53,55–62,64]. One study applied a longer exposure time in a control group than in the intervention group (420 s vs. 360 s both at 50°C) [7], while another study applied a higher temperature during a preliminary trial compared to the intervention trial (300 s at 49°C vs. 300 s at 47°C) [11].

Contact thermode surface area: The most commonly applied active thermode surface area were 12.5 cm² (41/64 [64%] studies) [1,5,6,10,12,13,16,18–21,29,32–34,36–39,41–44,46–62,64], 3.75 cm² (10/64 [16%] studies) [7,22–26,30,31,35,40], and 9 cm² (5/64 [8%] studies) [2,3,14,15,27]. The remaining 8/64 (13%) studies used active areas ranging from 0.3–10.2 cm² [4,8,9,11,17,28,45,63].

Induction site of CBI: Induction sites were the calf (46/64 [72%] studies) [1,2,5–7,10,12,13,16,20–26,29–44,46,47,49,50,52–60,64], volar forearm (12/64 [19%] studies) [3,4,8,9,11,17,19,28,48,61–63], thigh (4/64 [6%] studies) [14,15,18,27], abdomen (1/64 [2%] studies) [51], or dorsum of the hand (1/64 [2%] studies) [45].

Contact thermode application pressure: Applied contact thermode pressures were reported in 34/64 (53%) studies [4–7,10–13,16,23,28–34,39,40,45–47,51–55,57–63], with a median (range) of 5 (1.3 to 26) kPa.

Pain ratings: In 41/64 (64%) studies, pain ratings were reported during CBI-induction. Pain intensity assessments were: in 36 studies with the visual analog scale (VAS) [1,3,6,10–16,18,19,21,27,29,32–34,36–39,41–44,50,51,56–62,64], 15 of which were an electronic visual analog scale [6,11–15,18,19,21,27,39,50,51,61,62]; in three studies a numeric rating scale [2,8,28]; one study a verbal rank scale [31]; and in one study a ‘magnitude estimation’ method [17].

Post-burn changes

This section describes the changes induced by the CBI as a conditioning stimulus.

Primary hyperalgesia area, thermal stimuli: Warmth detection thresholds were generally not altered [1,5,41,49,54,55,58–60], but in five studies [16,32,33,42,60] increased post-CBI. In these studies, the duration of the change was less than 1 h [16,33,60]. Only one study observed a significant numerical increase in cool detection threshold following the CBI [33], while ten studies observed no post-CBI changes in cool detection threshold [16,41–43,49,54,58–60,64]. A total of 37 studies reported primary hyperalgesia to heat stimulation after the CBI, assessed as reduced heat pain threshold (HPT) or increased suprathreshold heat pain response [1,5–13,16,17,20,21,23–26,28,32–35,37,41,42,49–60,64], while two studies did not report any sensory changes [4,43]. Primary hyperalgesia lasted between 24–48 h post-CBI in one study (300 s at 49°C, 3.75 cm²) [23].

Primary hyperalgesia area, mechanical stimuli: Three studies investigated tactile detection thresholds and found no post-CBI sensory changes [53–55]. Post-CBI primary hyperalgesia to punctate mechanical stimuli was a consistent finding [1,4,10,11,16,23,24,26,29,32–35,41,42,47–49,53–60,62,64].

Secondary hyperalgesia, thermal/electrical stimuli: Secondary hyperalgesia to heat was observed in two studies [34,62], but this finding was not corroborated by four other studies [7,49,54,55]. Further, Aδ-fibers, but not C-fibers, were found to be sensitized to short radiant heat stimuli in the primary hyperalgesia area 24 h post-CBI, while no sensitization was present in the SHA [50]. Hyperalgesia to electrical stimulations was induced in the SHA in one study [62], but was not corroborated by another [29].

Secondary hyperalgesia, mechanical stimuli: A total of 15 studies [1,4,10,11,16,26,32–34,37,38,41–43,52,54,64] assessed SHAs to punctate mechanical stimulation during baseline conditions while 28 studies [5–7,12,13,20,21,23,24,28,29,35,36,44,46–51,53,55–60,62] assessed post-CBI areas without baseline assessments. In all studies the CBI induced robust SHA to punctate mechanical stimuli, with few studies reporting sustained SHA at 24 h (300 s at 49°C, 3.75 cm²) [23,26]. Areas of allodynia, during or after the CBI, were assessed in 25 studies [4,6,7,10,12,13,16,19–21,23,28,32–34,36,37,39,49,54,55,58,60–62]. Allodynia, tested by brush, developed shortly after the start of the CBI induction, but was generally more evanescent than SHA to punctate mechanical stimuli.

Temporal summation: Studies evaluated the following stimulation modalities: electrical [29,62], thermal [62], punctate mechanical [47,48,53–55,62], and mechanical impact [62]. Temporal summation was generally demonstrated post-CBI. Further, temporal summation to thermal stimuli did not increase post-CBI [62].

Objective inflammatory variables: Erythema was measured in eleven studies and was generally long-lasting (up to 48 h) [1,23,24,26,33,35,36,41,58,59,64]. Blood flow was increased in the primary CBI-area [4,46]. Skin temperatures were increased in four studies [46,54,55,59], although, unaltered in one study [5]. Skin temperatures returned to baseline values 60 min post-CBI in the primary hyperalgesia area, while temperatures concomitantly were increased outside the CBI-area and then returned to baseline after 30 min [46]. An area of flare was reported in six studies [4,7,22,28,46,62]. Flare was not present 160 min post-CBI [7]. Dermal thickness, measured by a high-resolution ultrasound scanner, was found to increase post-CBI for up to 360 min [1,64].

Adverse effects: In 19/64 (30%) studies, blistering was reported [7,22–26,29–36,39,42,46,49,60]. In 21/64 (33%) studies the presence of blistering was examined and did not occur [5,6,9–13,16–18,38,41,47,48,50–55,62], while in 23/64 (36%) studies blistering was not examined, nor reported [1–4,8,14,15,19–21,27,28,37,40,43–45,56–59,61,63,64]. Three studies reported slight localized skin color changes in 25% of subjects persisting for three weeks [32–34], while hyperpigmentation occurred in one subject 23 days post-CBI [38].

Study characteristics

Study characteristics are presented in Table 2.

Table 2. Study characteristics.

First author	Year	Study design	N (M/F)	Age (years)	Objective	Outcomes measured	Sample size estimate
Intervention
Dahl J [7]	1993	R, PD, C/I-2S	18/0^¤	Md (Rng): 27 (22–39)	Effect of pre- and post-burn lidocaine on hyperalgesia	WDT_in/out, HPT_in/out, P-SHA, B-SHA, Flare	NR
Møiniche S [22]	1993	U, R, OC, 2-A, 1-S, BB	B₁: 8/0 B₂: 8/0	B₁/B₂: $\bar{M}$ (Rng): 33 (26–44)	Effect of EMLA (B₁) and bupivacaine (B₂) on inflammation	B₁/B₂: Flare, Blistering	PPA
Møiniche S [25]	1993	DB, R, PC, 1-S, BB	12/0	$\bar{M}$ (SE): 33 (3)	Effect of local morphine on hyperalgesia	HPT, PPT	NR
Møiniche S [24]	1993	DB, R, PC, 1-S, BB	11/1	$\bar{M}$ (Rng): 33 (21–46)	Effect of topical piroxicam gel on hyperalgesia and inflammation	HPT, HPTo, P-SHA, MPT, EI, Blistering	NR
Brennum J [5]	1994	U, R, OC, 2-WX, BB^¶¶	5/5	$\bar{M}$ (Rng): 26 (22–31)	Effect of pre- vs. post-CBI epidural morphine on hyperalgesia	B-SHA, P-SHA, HPT, HPTo, WDT, Flare, ST	NR
Møiniche S [26]	1994	DB, R, PC, 1-S, BB	10/2	Md (Rng): 27 (21–45)	Effect of ketorolac gel on hyperalgesia and inflammation	HPT, HPTo, P-SHA, MPT, EI, Blistering	PPA
Pedersen JL [35]	1994	DB, R, PC, 1-S, BB	10/2	Md (Rng): 31 (23–44)	Effect of topical clobetasol propionate on hyperalgesia and inflammation	HPT, HPTo, P-SHA, MPT, EI, Blistering	NR
Ilkjær S [13]	1996	DB, R, PC, 3-WX	19/0	Rng: 20–31	Effect of ketamine on hyperalgesia	HPT, P-SHA, B-SHA, CBI-pain	NR
Lundell JC [17]	1996	DB, R, PC, 1-S, BB	10^‡‡	NR	Effect of ketorolac on hyperalgesia	HPT, H-pain, CBI-pain	NR
Pedersen JL [30]	1996	DB, R, PC, 1-S, BB	12/0	Rng: 22–47	Effect of EMLA on late hyperalgesia and inflammation	HPT, P-SHA, MPT, EI, Blistering	PMDD
Pedersen JL [31]	1996	U, R, OC, 1-S, BB	18/2^¤¤	Rng: 22–46	Effect of a preemptive nerve block on late hyperalgesia and inflammation	P-SHA, MPT, CBI-pain, EI, Blistering	NR
Warncke T [52]	1996	B₁: DB, R, PC, 1-S, BB B₂: DB, R, PC, 2-WX	B₁: 8/2 B₂: 8/12	B₁: $\bar{M}$ (Rng): 24 (21–37) B₂: $\bar{M}$ (Rng): 24 (21–40)	Effects of topical (B₁) or oral (B₂) ibuprofen on hyperalgesia	B₁/B₂: HPT, HPTo, P-SHA,	PPA
Ilkjær S [12]	1997	DB, R, PC, 3-WX	25/0	$\bar{M}$ (Rng): 24 (21–28)	Effect of dextromethorphan on hyperalgesia	HPT, P-SHA, B-SHA, CBI-pain	NR
Pedersen JL [36]	1997	SB, R, PC, 1-S, BB	21/3^†	R: 22–46	Effect of a lumbar sympathetic plexus block on hyperalgesia and inflammation	CBI-pain, MPT, HPT, H-pain, P-SHA, B-SHA, EI, ST	PMDD
Petersen KL [39]	1997	DB, R, PC, 2-WX	20/0	Rng: 19–31	Effect of ibuprofen on hyperalgesia	P-SHA, B-SHA, B-pain_out, CBI-pain	NR
Warncke T [53]	1997	DB, R, A/IC^†††, 2-WX, BB	10/0	Md: 22	Effect of ketamine on hyperalgesia and TS in the SHA compared to lidocaine and placebo	WDT_in/out, HPT_in/out, MPT_in/out, TDT_in/out, P-SHA, TS_M,out, ST	NR
Warncke T [54]	1997	DB, R, PC, 3-WX	10/2	$\bar{M}$ (Rng): 22 (20–29)	Effects of morphine and ketamine on hyperalgesia and TS in the SHA	B-SHA, CDT, CPT, HPT_in/out, MPT, TDT, P-SHA, ST, WDT, TS_M,out	NR
Pedersen JL [32]	1998	DB, R, SyC, PC, 3-WX	12/3	Rng: 26–48	Effect of local ketamine on hyperalgesia	WDT, HPT, H-pain, P-SHA, MPT, M-pain_in/out, B-SHA, CBI-pain	PMDD
Hammer NA [10]	1999	DB, R, PC, 2-WX	17/3	Rng: 22–48	Effect of riluzole on hyperalgesia	HPT, H-pain_short, H-pain_long, P-SHA, B-SHA, MPT, M-pain_in/out, CBI-pain	NR
Mikkelsen S [20]	1999	DB, R, PC, 3-WX	23/0	NR	Effect of naloxone on the anti-hyperalgesic effects of ketamine	HPT, P-SHA, B-SHA	NR
Sjölund KF [49]	1999	DB, R, PC, 2-WX	5/5	Rng: 19–31	Effect of adenosine on hyperalgesia and detection thresholds	B-SHA, CDT_in/out, HPT_in/out, H-pain_in/out, M-pain_in/out, MPT_in/out, P-SHA, WDT_in/out	NR
Holthusen H [11]	2000	DB, R, PC, 3-WX	6/0	Rng: 27–43	Effect of pre- vs. post-CBI lidocaine on hyperalgesia	WDT, HPT, P-SHA, MPT, TDT, CBI-pain, Flare	NR
Lillesø J [16]	2000	DB, R, PC, SyC, 3-WX	16/2	Rng: 22–48	Effect of morphine on hyperalgesia	WDT, HPT, H-pain, CDT, P-SHA, B-SHA, MPT, M-pain_in/out, CBI-pain	NR
Mikkelsen S [21]	2000	DB, R, PC, 3-WX	24/0	NR	Effect of oral morphine on hyperalgesia	HPT, P-SHA, B-SHA, CBI-pain	NR
Warncke T [55]	2000	DB, R, PC, 3-WX	11/1	$\bar{M}$ (Rng): 24 (21–29)	Effects of morphine and ketamine on hyperalgesia and detection thresholds	B-SHA, HPT_in/out, MPT_in/out, TDT, P-SHA, ST_in/out, WDT, TS_M,out	NR
Brennum J [6]	2001	DB, R, PC, 3-WX	24/0	$\bar{M}$ (Rng): 24 (20–31)	Effect of naloxone on hyperalgesia	B-SHA, P-SHA, HPT, H-pain_short/long, CBI-pain	PPA
Werner MU [60]	2001	DB, R, PC, 2-WX	22/0	Rng: 20–29	Effects of gabapentin on hyperalgesia	CBI-pain, CDT, HPT, MPT, M-pain_in/out, WDT, P-SHA, B-SHA	ASE/ PMDD
Werner MU [58]	2002	DB, R, PC, 2-WX	22/0	IQR: 25–26	Effect of systemic dexamethasone on hyperalgesia and thermal detection thresholds	CBI-pain, CDT, H-pain, HPT, M-pain, MPT, P-SHA, B-SHA, EI, WDT	ASE
Werner MU [59]	2002	SB, R, ShC, 1-S, BB	24/0	NR	Effects of local cooling on hyperalgesia and inflammation	CBI-pain, CDT, HPT, MPT, M-pain_in/out, P-SHA, EI, ST_in/out, WDT	ASE
Schulte H [47]	2004	DB, R, PC, 3-WX	6/5	$\bar{M}$ (Rng): 36 (22–50)	Synergistic effects of morphine and ketamine	MPT_in/out, P-SHA, TS_M,in/out, TDT_in/out	ASE
Schulte H [48]	2005	DB, R, A/IC^§§§, 3-WX	8/8	$\bar{M}$ (Rng): 29 (25–42)	Effect of morphine and alfentanil on hyperalgesia	MPT_in/out, P-SHA, TS_M,in/out	NR
Robertson L [63]	2007	DB, R, PC, 1-S, BB	9/15	Md (Rng): 25.5 (17–39)	Effect of local fentanyl and naloxone on hyperalgesia	H-pain, HPT, M-pain	NR
Stubhaug A [51]	2007	DB, R, PC, 3-WX	12/0	$\bar{M}$ (SD): 23 (2)	Effect of methylprednisolone and ketorolac on hyperalgesia	CBI-pain, HPT, P-SHA	ASE
Ravn P [43]	2013	DB, R, PC, 5-WX	14/13^††	$\bar{M}$ (SD): 25 (4)	Differences in anti-hyperalgesic effects of morphine and buprenorphine; relation between opioid effect and pain sensitivity	WDT, HPT, CDT, P-SHA, MPT, CBI-pain	ASE
Andersen LPH [1]	2015	DB, R, PC, 3-WX	29/0	$\bar{M}$ (CI): 26 (25–28)	Effect of melatonin on hyperalgesia and inflammation	CBI-pain, MPT_in/out, P-SHA, PPT, PPTo, HPT, WDT, EI, DT	ASE/PPA^‡
Rasmussen VM [41]	2015	U, R, OC, 2-WX	17/0	$\bar{M}$ (CI): 28 (25–30)	Effect of hyperbaric oxygen on hyperalgesia	WDT, HPT, CDT, P-SHA, MPT, EI, CBI-pain	ASE
Wahl AM [64]	2019	SB, R, OC, 2-WX	19/0	Md (Rng): 27.5 (21–56)	Effects of hyperbaric oxygen on hyperalgesia post-CBI	WDT, HPT, CDT, P-SHA, MPT, EI, CBI-pain, DT	ASE
Non-intervention
Methodological
Møiniche S [23]	1993	EXP, 2-S, TR	8/0	Md (Rng): 28 (20–46)	Examine time course of primary and secondary hyperalgesia	HPT, HPTo, P-SHA, B-SHA, MPT, EI	NR
Pedersen JL [33]	1998	EXP, 3-S, TR	11/1	Rng: 24–47	To determine the within-day and between-day reproducibility of the CBI-model	WDT, HPT, H-pain, CDT, P-SHA, B-SHA, MPT, CBI-pain, EI	ASE
Yucel A [61]	2001	EXP	7/3^¤¤¤	Rng: 21–34	Effect of pre- and post-injury heat conditioning on hyperalgesia and inflammation in the CBI-model and the topical/intradermal capsaicin model	B-SHA, SBF_in/out, P-SHA, ST, Flare, CBI-pain	NR
Yucel A [62]	2004	EXP, R, 2-S-CAP/CBI	9/3	$\bar{M}$ (VA NR): 23.6 (1.8)	Comparison of TS between the CBI-model and the heat/capsaicin model	B-SHA, CBI-pain, EPT-SS_out, EPT-RS_out, HPT-SS_out, HPT-RS_out, MI-pain_in/_out, M-pain_in/_out, P-SHA, TS_M,in/out, TS_I,in/out, TS_E,out, TS_H,out, Flare	NR
Naert ALG [27]	2007	EXP, TR^¶¶¶	31/27	$\bar{M}$ (SEM): 26 (0.9)	Characterization and validation of the CBI-model as a tonic heat pain model	HPT, HPTo, H-pain, CBI-pain	NR
Bishop T [4]	2009	EXP, 3-B	8/4^*	$\bar{M}$ (SEM): 26.6 (2.4)	To compare sensory changes of the UVB model to the CBI-model and topical capsaicin model	HPT, P-SHA, B-SHA, MPT, Flare, SBF	NR
Ringsted TK [44]	2015	EXP, 2-S, TR	11/12	$\bar{M}$ (CI): 23.8 (23.2–24.3)	To compare the SHA between 4 stimulators; to examine inter-day and inter-observer differences of the SHA	P-SHA, CBI-pain	ASE
Physiological
Pedersen JL [29]	1998	EXP, 1-S	11/1	Rng: 23–37	Comparison of TS in normal and hyperalgesic skin	P-SHA, MPT, CBI-pain, EPT-SS_in/out, EPR_in/out, TS_E,in, TS_E,out	PMDD
Pedersen JL [34]	1998	EXP, 1-S	12/3	Rng: 26–48	To examine the evidence for heat hyperalgesia within the mechanical SHA	HPT, H-pain_in/out, P-SHA, B-SHA, MPT, M-pain_in/out, CBI-pain	NR
Schulte H [46]	2004	EXP, 1-S	9/11	$\bar{M}$ (R): 37 (19–58)	Examine correlation between SBF and P-SHA	SBF_area, P-SHA^*, ST_in/out, Flare	NR
Norbury TA [28]	2007	EXP, 1-S^**	0/196	Rng: 19–76	To investigate the heritability of pain sensitivity in a twin study	HPT, P-SHA, B-SHA, CBI-pain, Flare	ASE
Drummond PD [8]	2008	EXP, PC, OC	25^‡‡	Rng: 18–58	To investigate the effect of noradrenaline efflux in the skin on the sensitivity to hyperalgesia	HPT, H-pain, CBI-pain, EPS	NR
Robertson L [45]	2008	DB, R, PC, 2-WX, BB	17/5	Md (Rng): 19 (17–39)	To investigate the effect of repeatedly immersing a CBI in cold water on heat-pain sensitivity	HPT, ST	NR
Drummond PD [9]	2009	2-EG-4-CBI, PC	10/24^***	Rng: 17–32	To investigate the nociceptive effects of α1- and α2-adrenoceptor agonists with and without prior α-adrenergic blockade	HPT, H-pain	NR
Kupers R [15]	2009	EXP	12/9^§	$\bar{M}$ (SD): 32.2 (8.9)	To investigate the correlation between 5-HT_2A receptor availability and tonic and phasic heat pain using PET	HPT, HPTo, H-pain, CBI-pain	NR
Petersen LJ [40]	2009	PD, 3-EG, 1-S	B₁: 6/0 B₂: 8/0 B₃: 8/0	Rng: 26–46	To study histamine release in human skin by microdialysis technique after a CBI	No QST	NR
Kupers R [14]	2011	EXP	13/8	$\bar{M}$ (SD): 32.6 (8.8)	To investigate the role of the SERT on pain during tonic and phasic heat using PET	HPT, HPTo, H-pain, CBI-pain	NR
Pereira MP [38]	2013	DB, R, PC, 2-WX	11/11	$\bar{M}$ (SD)_M: 24.5 (2.0) $\bar{M}$ (SD)_F: 23.0 (1.2)	To examine if naloxone reinstates hyperalgesia after the resolution of a CBI	WDT, HPT, P-SHA, MPT, CBI-pain	ASE
Asghar MS and Pereira MP [2]	2015	EXP	HS: 6/14 LS: 12/8^§§	$\bar{M}$ (SD)_HS: 24.3 (2.3) $\bar{M}$ (SD)_LS: 24.2 (2.6)	To compare structural and functional characteristics of brain activity and anatomy in HS and LS using fMRI	P-SHA, M-pain_in/out, CBI-pain	ASE
Pereira MP [37]	2015	DB, R, PC, 2-WX	12/0	$\bar{M}$ (CI): 23.8 (22.8–24.9)	To examine if naloxone reinstates hyperalgesia after the resolution of a CBI	WDT, HPT, P-SHA, B-SHA, MPT, CBI-pain	ASE/PSE
Slimani H [50]	2018	SB, R, ShC, PD	20/0	$\bar{M}$ (VA NR)_EG: 23.8 (1.5) $\bar{M}$ (VA NR)_CTRL: 24.5 (4.5)	Assess changes in reaction time and sensory detection thresholds in Aδ- and C-fibers after a CBI	CBI-pain, HPT_AF,in/out, HPT_CF,in/out, H-pain_AF,in/_out, H-pain_CF,in/out, P-SHA, RTFD_AF,in/out, RTFD_CF,in/out	NR
Predictive
C₁: Werner MU [57] C₂: Werner MU [56]^¶	C₁: 2003 C₂: 2004	C₁: EXP, PD, 2-S C₂: EXP	C₁: Pt: 14/4, CTRL: 13/1 C₂: 14/6	C₁: Md (IQR)_Pt: 27 (25–32); Md (IQR)_CTRL: 31 (27–40) C₂: Md (IQR): 28 (24–33)	C₁: To compare the hyperalgesic response before and after arthroscopic knee surgery C₂: Effect of pre-operative hyperalgesic response to predict postoperative pain ratings in knee surgery patients	C₁/C₂: CBI-pain, H-pain, HPT, M-pain, MPT, P-SHA	C₁: ASE C₂: NR
Ravn P [42]	2012	EXP, 2-S	50/50	$\bar{M}$ (SD): 23.7 (3.6)	Evaluation of QST, psychometrics, gender, and anthropometrics ability to predict pain during a CBI	WDT, HPT, CDT, P-SHA, MPT_in/out, CBI-pain	NR
Lunn TH [18]	2013	Prospective, consecutive, observational, cohort	47/50	$\bar{M}$ (Rng): 66 (39–89)	To assess if short and long heat stimulation can predict postoperative pain after total knee arthroplasty	CBI-pain, H-pain	ASE
Miscellaneous
Matre D [19]	2006	PD, 3-S, PAS	PL: 10/9 CTRL: 7/3	Rng_PL: 20–44 Rng_Con: 20–45	Effect of a placebo condition on hyperalgesia	P-SHA, B-SHA, MPT, M-pain, CBI-pain	NR
Aslaksen PM [3]	2008	R, 2-S, OC, PAS	31/32	$\bar{M}$ (SD)_M: 25.4 (5.4) $\bar{M}$ (SD)_F: 23.1 (4.7)	Effect of a placebo condition on pain during a CBI and negative emotions	CBI-pain	NR

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A/IC = active and inactive placebo-controlled; AF = A-fibers; ASE = a priori sample size estimate; B-pain = motor brush-evoked pain ratings; B-SHA = brush secondary hyperalgesia area (allodynia); CBI = contact burn injury; CBI-pain = CBI-induced pain ratings; BL = baseline; C/I-2S = 2 groups (1 control and 1 intervention) with 2 sessions per group; CDT = cool detection threshold; CF = C-fibers; CI = 95% confidence interval; DB = double-blind; DT = dermal thickness; EG = experimental group; EI = erythema index; EPR = electrical pain response to a single stimulus; EPS = electrically-evoked pain sensations; EPT = electrical pain threshold; CTRL = control; EPT-RS = electrical pain threshold repetitive stimuli; EPT-SS = electrical pain threshold single stimulus; EXP = exploratory; F = female; Flare = area of flare; fMRI = functional magnetic resonance imaging; H-pain = heat-evoked pain rating; HPT = heat pain threshold; HPTo = heat pain tolerance; HS = high-sensitizers; I = intervention; IQR = interquartile range; LS = low-sensitizers; $\bar{M}$ = mean; M = male; M-pain = punctate mechanical-evoked pain rating; MI-pain = mechanical impact-evoked pain ratings; Md = median; MPT = mechanical pain threshold; NA = not applicable; NR = not reported; OC = open control; P-SHA = punctate secondary hyperalgesia area; PAS = placebo analgesia study; PC = placebo-controlled; PD = parallel design; PET = positron emission tomography; PL = placebo; PMDD = post hoc minimal detectable differences; PPA = post hoc power analysis; PPT = pressure pain threshold; PPTo = pressure pain tolerance; PSE = post hoc sample size estimate; Pt = patients; QST = quantitative sensory testing; R = randomized; Rng = range; RTFD = reaction time frequency distribution; SB = single-blind; SBF = skin blood flow; SE = standard error; SERT = serotonin transporter; SHA = secondary hyperalgesia area; ShC = sham-controlled; ST = skin temperature; SyC = systemic-controlled; TDT = tactile detection threshold; TR = test-retest; TS_M/TS_E/TS_I/TS_H = temporal summation to punctate mechanical/electrical/mechanical impact/heat stimulation; U = unblinded; VA = variance; WDT = warmth detection threshold; 1-S/2-S/3-S = one-/two-/three-session study; 2-A = 2 arm study design; 2-EG-4-CBI = 2 experimental groups with 4 burn injury sites in each group; 2-S-CAP/CBI = 2 sessions with intradermal capsaicin in one session and a burn injury in the other; 2-WX/3-WX/4-WX/5-WX = two-/three-/four-/five-way crossover design; 3-B = 3 block study; 3-EG = 3 experimental groups.

¤ n = 8/12 in control/intervention study; 2 subjects excluded from intervention study.

¤¤ 6 subjects excluded from hyperalgesia comparisons.

¤¤¤ only subjects from burn injury group.

† n = 16 after exclusion.

†† subjects selected based on highest and lowest pain scores during a burn injury in another study.

††† active placebo: Lidocaine (SC 30 mg).

‡ post hoc power analysis performed because of incorrect a priori sample size estimate.

‡‡ total subjects, gender not reported.

§ 3 subjects withdrew from analysis.

§§ categorization into high- and low-sensitizers based on SHAs after a burn injury on the screening day.

§§§ active placebo: Midazolam (IV 20 μg/kg).

¶ study C₂ included 17 of the same patients as the companion paper study C₁.

¶¶ burn injuries were not induced at the same time-point.

¶¶¶ only 12 subjects retested 3 months later.

* only subjects from study block with burn injury.

** variability and reliability were tested in 10 individuals on two separate days.

*** α1-adrenoceptor (n = 19); α2-adrenoceptor (n = 15). A subscript was added to the different tests to indicate whether they were measured in the primary hyperalgesia area (in) or the SHA (out). A_1-4: Numbering applied to this letter indicates different interventions in the same study group of a particular study. B_1-3: Numbering applied to this letter indicates different interventions or experimental setups in different study groups of the same study. C_1-2: Numbering applied to this letter indicates different companion papers investigating parts or all of the same study group.

Intervention studies

The 37 studies [1,5–7,10–13,16,17,20–22,24–26,30–32,35,36,39,41,43,47–49,51–55,58–60,63,64] evaluated ten drug groups (antiarrhythmic agents [49], gabapentinoids [60], glucocorticoids [35,51,58], glutamate receptor antagonists [10], local anesthetics [7,11,22,30], melatonin [1], N-methyl-D-aspartate (NMDA) receptor antagonists [12,13,20,21,32,47,53–55], non-steroidal anti-inflammatory drugs (NSAIDs) [17,24,26,39,51,52], opioids [5,16,25,43,47,48,54,55,63], and opioid antagonists [6]), along with hyperbaric oxygen [41,64], local cooling [59], and nerve blocks [31,36].

The total number of per-protocol subjects was 641, with a median of 17 (12 to 22) subjects per study. All but one study mentioned the ratio of males to females [17], and another study only described the intention-to-treat group’s male to female ratio [36]. For the remaining studies, a gender ratio (males/females) of 6.4 (532/83) was present. A total of eleven studies reported the bodyweight of subjects [1,5,22,24–26,35,41,43,51,64], while four of these reported BMI [1,41,43,64]. Nine studies included an a priori sample size estimate [1,41,43,47,51,58–60,64]. Four studies [6,22,26,52] performed post hoc power-analyses, while an additional four studies estimated post hoc minimal detectable differences for all outcomes [30,32,36,60]. After an incorrect a priori sample size estimate, one study presented a post hoc power analysis [1].

All studies were described as randomized. A total of 29/37 studies were double-blind [1,6,10–13,16,17,20,21,24–26,30,32,35,39,43,47–49,51–55,58,60,63], and all were, along with two single-blinded studies [36,64], placebo-controlled. Two of the placebo-controlled studies used both active and inactive placebos [48,53]. The non-pharmacodynamic studies used control-conditions (i.e., ambient atmospheric pressure [41,64] and ambient temperature of contact thermode [59]).

Among the 34 studies involving drug administration, seven studies evaluated the effect of several drugs [22,43,47,48,51,54,55], and three studies administered naloxone along with other drugs to examine any opioid-mediated effects [16,20,63]. Multiple drug dosing was evaluated in seven studies [1,6,12,13,21,43,48].

Methodological quality was assessed by the Oxford Quality Scoring System [75]. The median (IQR) score for the 37 intervention studies was 2 (2 to 3). Fifteen studies had a high-quality score ≥ 3 (Table 3) [1,6,11,17,20,21,41,43,48,51,52,54,55,58,64].

Table 3. Intervention study results.

First author	Intervention type	Time of intervention	Specific outcomes	Main outcomes	Quality score
Pharmacodynamic
Antiarythmic agents
Sjölund KF [49]	Adenosine (IV/7.2 mg/kg)	-15´	↓P-SHA, →B-SHA, →\|CDT_in/out\|_, →H-pain, →HPT_in/out, →M-pain, →MPT_in/out, →WDT_in/out	Adenosine reduced SHAs without reducing primary hyperalgesia	2
Gabapentinoids
Werner MU [60]	Gabapentin (oral/1200 mg)	-3h	↑MPT, →B-SHA, \|→CDT\|, →HPT, →M-pain_in/out, →P-SHA, →WDT	Gabapentin increased only MPT without decreasing M-pain	2
Glucocorticoids
Pedersen JL [35]	Clobetasol propionate (topical/0.2–0.3 g 0.05%)	-60´	→HPT, →HPTo, →P-SHA, →MPT, →EI, →Blistering	Topical glucocorticoid had no effect on hyperalgesia or inflammation	2
Werner MU [58]	Dexamethasone (IV/8 mg)	~-2h	→B-SHA, \|→CDT\|, →H-pain, →HPT, →M-pain, →MPT, →P-SHA. →EI, →WDT	Dexamethasone did not reduce pain, sensory thresholds, or erythema	4
Glutamate receptor antagonists
Hammer NA [10]	Riluzole (oral/100 mg)	-90´	→HPT, →H-pain_short/long, →P-SHA, →B-SHA, →MPT, →M-pain_in/out, →CBI-pain	Riluzole did not reduce primary hyperalgesia or SHAs	2
Local anesthetics
Dahl J [7]	Lidocaine (SC/5-6 ml 1%)	Pre-CBI: -5´ Post-CBI: 35´	Pre-CBI injection compared to post-CBI for all ↓P-SHA¤, ↓B-SHA^¤, ↓Flare, →WDT_in/out, →HPT_in/out	Pre-CBI lidocaine more effectively reduced SHAs than post-CBI lidocaine but only shortly	2
Møiniche S [22]	B₁: EMLA (topical/2 g 5%) B₂: Bupivacaine (SC/8 mL 0.5%)	B₁: -90´ B₂: -15´	B₁/B₂: →Flare, →blistering	No anti-inflammatory effects of topical EMLA or subcutaneous bupivacaine	1
Pedersen JL [30]	EMLA (topical/2 g 5%)	0´	→HPT, →P-SHA, →MPT, →EI, →blistering	Topical EMLA did not alter hyperalgesia or inflammation	2
Holthusen H [11]	Lidocaine (IV/317.5 mg)	Pre-CBI: -30´ Post-CBI: 0´	↓P-SHA^¤¤, →MPT, →TDT, →HPT, →WDT, →Flare, →CBI-pain	Pre-CBI lidocaine reduced SHAs compared to placebo without being superior to post-CBI lidocaine	3
Melatonin
Andersen LPH [1]	Melatonin (A₁: IV 100 mg; A₂: IV/10 mg)	-60´	A₁/A₂: →WDT, →HPT, →P-SHA, →MPT_in, →MPT_out, →PPT, →PPTo, →CBI-pain, →EI, →DT	Melatonin did not reduce hyperalgesia or inflammation	5
Nerve blocks
Pedersen JL [31]	Sapheneous nerve block (lidocaine 9 ml 1%)	CBI induced upon complete block	↓P-SHA, ↑MPT, →EI, →Blistering	A pre-CBI nerve block reduced primary hyperalgesia and SHAs after return of cold sensation	1
Pedersen JL [36]	Sympathetic lumbar nerve block (bupivacaine 0.5% 10 ml)	~-45´	↑ST, →CBI-pain, →MPT, →HPT, →H-pain, →P-SHA, →B-SHA, →EI	A pre-CBI sympathetic nerve block did not alter pain or hyperalgesia	2
NMDA receptor antagonists
Ilkjær S [13]	Ketamine (A₁: IV/0.49 mg/kg in 150´; A₂: IV/0.98 mg/kg in 150´)	-20´	A₁: ↓B-SHA^¤¤¤, →CBI-pain, →P-SHA, →HPT A₂: ↓CBI-pain, ↓P-SHA, ↓B-SHA, ↑HPT	Ketamine reduced primary hyperalgesia and SHAs more pronounced with high doses	2
Ilkjær S [12]	Dextromethorphan (A₁: oral/60 mg; A₂: oral/120 mg)	-120´	A₁: →P-SHA, →CBI-pain, →B-SHA, →HPT A₂: ↓P-SHA, →CBI-pain, →B-SHA, →HPT	High dose dextromethorphan slightly reduced SHA without reducing primary hyperalgesia	2
Warncke T [53]	Ketamine (SC/4.98 mg)	-20´	Only compared to inactive placebo ↑HPT_in, ↑WDT_in^††, ↑MPT_in, ↓P-SHA, ↓TS_M,out, →TDT_in	Local ketamine showed long-lasting inhibition of the development of SHA	2
Pedersen JL [32]	Ketamine (SC/7.5 mg)	-40´ and -7´	↑HPT^‡, ↑MPT^‡, ↓M-pain_in^†††, ↓CBI-pain, →M-pain_out, →P-SHA, →B-SHA, →WDT, →H-pain	Subcutaneous ketamine had brief local analgesic effects	2
Mikkelsen S [20]	A₁: Naloxone (IV/0.9 mg in 30 min) → Ketamine (IV/0.375 mg/kg in 30 min) A₂: Saline → Ketamine (IV/0.375 mg/kg in 30 min)	75´	A₁/A₂: ↓P-SHA, ↓B-SHA, →HPT	Ketamine reduced SHAs regardless of whether naloxone or placebo was infused prior to ketamine	4
Mikkelsen S [21]	Ketamine (A₁: oral/0.5 mg/kg; A₂: oral/1.0 mg/kg)	-20´	A₁/A₂: →HPT, →P-SHA, →B-SHA, →CBI-pain	Oral ketamine did not reduce primary hyperalgesia or SHAs	5
NSAIDs
Møiniche S [24]	Piroxicam (topical/1 g 0.5%)	-90´	→HPT, →HPTo, →P-SHA, →MPT, →EI, →Blistering	Piroxicam gel had no effect on hyperalgesia or inflammation	2
Møiniche S [26]	Ketorolac (topical/0.75 g 1%)	-90´	→HPT, →HPTo, →P-SHA, →MPT, →EI, →Blistering	Topical ketorolac did not reduce hyperalgesia	2
Lundell JC [17]	Ketorolac (intradermally/0.3 mg)	~-50´	↓H-pain^‡‡, →HPT, →CBI-pain	Ketorolac decreased the heat pain response in the range of 46-49°C	4
Warncke [52]	Ibuprofen (A₁: topical/3 g 5%; A₂: oral/600 mg)	A₁: 30´ A₂: -70´	A₁/A₂: →HPT, →HPTo, →P-SHA	No anti-hyperalgesic effect of topical or oral ibuprofen	3
Petersen KL [39]	Ibuprofen (oral/600 mg)	-60´	↓B-pain_out, →CBI-pain, →P-SHA, →B-SHA	Oral ibuprofen had weak effect on allodynia	2
Opioids
Møiniche S [25]	Morphine (SC/2 mg)	30´	↑HPT, ↑PPT^‡‡‡	Local morphine reduced primary hyperalgesia, mainly to heat	2
Brennum J [5]	Morphine (epidural/4 mg)	30´^§	Compared to control for both pre- and post-CBI assessments ↑WDT, ↓P-SHA, ↓B-SHA, →HPTo	Pre- and post-CBI morphine attenuated SHAs comparatively	1
Lillesø J [16]	Morphine (SC/2 mg)	-60´	↑P-SHA, ↑B-SHA, →CBI-pain, →MPT, →M-pain_in/out, →WDT, \|→CDT\|, →HPT, →H-pain	Local injection of morphine may have contributed to hyperalgesia	2
Schulte H [48]	Morphine (A₁: IV/0.14 mg/kg; A₂: IV/0.28 mg/kg) A₃: Alfentanil (IV/73 μg/kg)	70´	A₁/A₂: →P-SHA, →MPT_in/out, →TS A₃: ↓P-SHA^¶, ↑MPT_in/out^¶, →TS	Alfentanil had anti-hyperalgesic effects, but no statistically significant dose-dependent effects of morphine were demonstrated	3
Robertson L [63]	A₁: Fentanyl (SC/10 μg) A₂: + pretreatment with naloxone (SC/80 μg)	45´	A₁: ↑HPT, →M-pain^§§§, →H-pain A₂: →HPT, →M-pain, →H-pain	Naloxone blocks the anti-hyperalgesic effects of fentanyl	2
Ravn P [43]	Buprenorphine (A₁: IV/0.3 mg/210 min; A₂: IV/0.6 mg/210 min) Morphine (A₃: IV/10 mg/210 min; A₄: IV/20 mg/210 min)	-140´	A₁: ↑\|CDT\|^¶¶, ↓CBI-pain, →P-SHA, →WDT, →HPT A₂: ↑\|CDT\|^¶¶, ↑HPT^¶¶¶, ↓CBI-pain^¶¶, →P-SHA, →WDT A₃: ↓\|CDT\|, →P-SHA, →WDT, →HPT, →CBI-pain A₄: ↑\|CDT\|, ↓CBI-pain, →P-SHA, →WDT, →HPT	No clear differences between morphine and buprenorphine in anti-hyperalgesia/analgesia profiles; no difference between high and low pain-sensitive subjects	5
Opioid antagonists
Brennum J [6]	Naloxone (A₁: IV/0.4 mg; A₂: IV/10 mg)	170´	A₁/A₂: →HPT, →H-pain_short/long, →P-SHA, →B-SHA	No dose of naloxone had effect on primary hyperalgsia or SHAs	3
Multimodal
Warncke T [54]	A₁: Morphine (IV/0.15 mg/kg) A₂: Ketamine (IV/0.15mg/kg)	50´	A₁: →WDT, →HPT_in/out, \|→CDT\|, →CPT, →TDT, →MPT_in/out, →B-SHA, →P-SHA, →ST, →TS_M,out A₂: ↓B-SHA, ↓P-SHA, ↓TS_M,out^*, →WDT, →HPT, \|→CDT\|, →CPT, →TDT, →MPT, →ST	Ketamine, and not morphine, reduced SHAs and the occurrence of TS	3
Warncke T [55]	A₁: Morphine (IV/0.205 mg/kg in 80 min) A₂: Ketamine (IV/0.39 mg/kg in 80 min)	-30´	A₁: ↓TS_M,out, ↓P-SHA, ↓B-SHA, →MPT_in^, →HPT_in/out, →WDT,→ST_in/out, →TDT, →MPT_out A₂: ↑MPT_in^*, ↑MPT_out ^¤¤¤¤, ↓TS_M,out, ↓P-SHA, ↓B-SHA, →HPT_in/out, →WDT, →ST_in/out, →TDT	Pre-treatment with morphine or ketamine reduced SHAs and TS	4
Schulte H [47]	A₁: Morphine (IV/0.1 mg/kg) A₂: Ketamine (IV/0.405 mg/kg) A₃: Both drugs	30´	A₁: →P-SHA, →MPT, →TS_M,in/out A₂: ↓P-SHA^††††, ↑MPT, →TS_M,in/out A₃: ↑MPT, ↓TS_M,in^†, ↓TS_M,out, →P-SHA	Ketamine and morphine reduced TS when co-administered, without affecting TS independently; ketamine transiently reduced SHAs	2
Stubhaug A [51]	A₁: Methylprednisolone (IV/125 mg) A₂: Ketorolac (IV/60 mg)	45´	A₁/A₂: ↓P-SHA	Both methylprednisolone and ketorolac decreased SHAs	5
Non-pharmacodynamic
Hyperbaric oxygen
Rasmussen VM [41]	Hyperbaric oxygen (100% O2, 2.4 ATM for 90 min; ambient pressure as control)	0´	↓P-SHA, →MPT, →CBI-pain, →EI, →WDT, →HPT, \|→CDT\|	Hyperbaric oxygen reduced SHA, with effect derived from the sequence starting with control	3
Wahl AM [64]	Hyperbaric oxygen (100% O₂, 2.4 ATM for 90 min; ambient pressure as control)	0´	↓P-SHA, →SE, →DT, →CDT, →MPT, →CBI-pain, ↓WDT, ↓HPT	Hyperbaric oxygen reduced SHA, with effect derived from the sequence starting with control	3
Local cooling
Werner MU [59]	Local cooling via contact thermode (12.5cm², 8°C, 30 min, 6.5kPa; dummy thermode as control)	8´	↑\|CDT\|^§§, ↓ST_out^§§, →HPT, →M-Pain_in/out, →MPT, →P-SHA, →EI, →ST_in, →WDT	Local cooling did not reduce inflammation or hyperalgesia	2

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B-pain = motor brush-evoked pain ratings; B-SHA = brush secondary hyperalgesia area (allodynia); CBI = contact burn injury; CBI-pain = CBI-induced pain ratings; CDT = cool detection threshold; DT = dermal thickness; EI = erythema index; EMLA = Eutectic mixture of local anesthetics; EPR = electrical pain response to a single stimulus; EPS = electrically-evoked pain sensations; EPT = electrical pain threshold; EPT-RS = electrical pain threshold repetitive stimuli; EPT-SS = electrical pain threshold single stimulus; Flare = area of flare; H-pain = heat-evoked pain rating; HPT = heat pain threshold; HPTo = heat pain tolerance; M-pain = punctate mechanical-evoked pain rating; MI-pain = mechanical impact-evoked pain ratings; MPT = mechanical pain threshold; P-SHA = punctate secondary hyperalgesia area; PPT = pressure pain threshold; PPTo = pressure pain tolerance; SBF = skin blood flow; SHA = secondary hyperalgesia area; ST = skin temperature; TDT = tactile detection threshold; TS_M/TS_E/TS_I/TS_H = temporal summation to punctate mechanical/electrical/mechanical impact/heat stimulation; WDT = warmth detection threshold.

¤ reduced by pre- compared to post-CBI only at 40´ and 70´ post-CBI, and not 100–190´ post-CBI and not by ANOVA 40–190´ post-CBI.

¤¤ only reduced by pre-CBI lidocaine compared to control.

¤¤¤ only short-term effect during infusion, significant at 110´ post-CBI.

¤¤¤¤ significant only during infusion.

† only significant effect at 15´ post-dosing (45´ post-CBI).

†† only significant at 30´ post-CBI.

††† only significant compared to systemic ketamine and only at 0´post-CBI.

†††† only significant effect at 45´ post-dosing (75´ post-CBI), not 75´ post-dosing.

‡ only significant at 0´post-CBI.

‡‡ no difference compared overall temperatures (P = 0.08), however, in the range of 46-49°C, ketorolac decreased pain response (P < 0.05; ANOVA); no benefit of treatment at high temperatures (e.g., 50°C and 51°C).

‡‡‡ only significant effect when analyzing relative changes non-parametric 2-way ANOVA; only significant at 30´ post-CBI when not analyzing relative changes.

§ only one injection, but this was at -150´ compared to second burn

§§ only significant effect at 10´ post-cooling.

§§§ decreased relative to naloxone treated site, but not pre- vs. post-drug.

¶ only significant at 155´ post-CBI during the infusion, and not at 275´ post-CBI after the infusion.

¶¶ significant compared to placebo and low-dose morphine.

¶¶¶ significant compared to placebo and both morphine doses.

* only significant at 65´ post-CBI, 15´ post-infusion.

** only short-term effect at 0´; not significant overall by ANOVA P = 0.18.

*** only significant until 30´ post-CBI, not at 110´ and 150´ post-CBI. Arrows indicate significant increases (↑) or decreases (↓), or no difference (→) after intervention compared to placebo if not otherwise stated. The Time of intervention column provides the timing of intervention administration in relation to the burn injury induction (time 0); negative values thus refer to a pre-CBI administration, and positive values refer to administration post-CBI (including 0´ which is immediately post-CBI).

Methodological studies. The seven studies [4,23,27,33,44,61,62] focused on characterizing the CBI as a model of tonic heat pain [27]; validating reproducibility [33]; evaluating the vascular and sensory effects of heat conditioning [61]; determining time-courses of hyperalgesia [23]; characterizing SHA assessments [44], and comparing the CBI-model to other models of evoked hyperalgesia [4,62].

The total number of per-protocol subjects was 135, with a median of 12 (11 to 18) subjects per study. The gender ratio (males/females) was 1.7 (85/50). Only one study included data on subjects’ height, weight, or BMI [44]. Two studies reported a priori sample size estimates [33,44].

Physiological studies. The fourteen studies [2,8,9,14,15,28,29,34,37,38,40,45,46,50] focused on comparing SHAs to areas of flare [46], the adrenergic system [8,9], the endogenous opioid system [37,38,45], heritability of pain responses [28], imaging [2,14,15], latent sensitization [37,38], local inflammatory mediators [40], nociceptive fibers [50], secondary hyperalgesia to heat [34], and temporal summation [29].

The total number of per-protocol subjects was 482, with a median of 21.5 (20 to 24) subjects per study. One study did not report the gender of subjects [8], but for the remaining studies, a gender ratio (males/females) of 0.6 (167/290) was obtained. Three studies provided height and weight of subjects [2,37,38], and one also reported BMI [37]. Four studies reported a priori sample size estimates [2,28,37,38], and one of these included a post hoc sample size estimate [37]. One study calculated post hoc minimal detectable differences for all outcomes [29].

Predictive studies. Three of the four predictive studies focused on patients undergoing knee surgery [18,56,57]: Two of these studies investigated the predictive potential of the CBI model [18,56] while the third investigated how surgery modulates hyperalgesic responses [57]. The fourth study evaluated the predictability of pain during a CBI, based on QST assessments [42].

The three knee surgery studies involved patients [18,56,57], while the fourth study included healthy subjects [42]. Accounting for duplicate subjects, the total number of per-protocol subjects was 232. The ratio between male and female subjects was 1.1 (124/108). One study provided height, weight, and BMI of subjects [42]. Two of the four studies reported a priori sample size estimates [18,57].

Study outcomes

Intervention studies

This subsection focuses on the efficacy of interventions in attenuating hyperalgesia, pain, and other inflammatory responses following a CBI. An overview of the intervention studies is presented in Table 3. In general, no intervention showed clear efficacy in attenuating CBI-induced hyperalgesia.

NMDA receptor antagonists: Ketamine reduced the SHA in four studies [13,53–55], while two studies found transient to no effects on hyperalgesia [21,32]. The effects of ketamine on SHAs were observed regardless of whether it was administered preemptively [13,53,55] or post-CBI [54]. Furthermore, ketamine reduced the SHA regardless of a preceding naloxone infusion, indicating that the effect of ketamine was not mediated by the endogenous opioid system [20]. Ketamine was claimed to act synergistically with morphine in reducing temporal summation [47]. Dextromethorphan, another NMDA receptor antagonist, marginally reduced the SHA [12].

Opioids: A preemptive infusion [55], but not a post-CBI infusion [47,48,54], of morphine, attenuated SHAs, and temporal summation. Epidural morphine injection reduced the SHA regardless of administration timing [5]. No difference was found between systemic buprenorphine or morphine administration on hyperalgesia, nor between the effect on high- and low pain-sensitizer subjects [43].

Glucocorticoids and NSAIDs: One comparative study found an effect of methylprednisolone and ketorolac, respectively, on reducing the SHA, with no statistical difference between the two drugs [51]. No other effects of glucocorticoids on hyperalgesia and inflammation were reported [35,58]. The effects of NSAIDs on heat pain perception were weak and observed exclusively within the range of 46°C to 49°C, but interestingly not at higher temperatures (50°C to 51°C) [17]. Pain intensity evoked by motor brush stimulation in the SHA was lower following ibuprofen compared to placebo, while the magnitude of SHA was unaltered [39]. No effect of topical NSAID on hyperalgesia and inflammatory variables has been observed [24,26,52].

Antiarrhythmics: Adenosine infusion reduced the SHA without reducing primary hyperalgesia to mechanical or thermal stimuli [49].

Nerve blocks: A saphenous nerve block was found to reduce primary hyperalgesia and SHAs [31], while a sympathetic nerve block did not alter pain or hyperalgesia [36]. These studies were not double-blinded.

Local anesthetics: Two studies evaluated the effect of administering intravenous [11] and subcutaneous [7] lidocaine pre- vs. post-CBI and found no clear superiority of one over the other [7,11]. EMLA-cream [22,30] and bupivacaine [22] had no clear effect on thermal hyperalgesia [30] nor any inflammatory variables [22,30].

Miscellaneous: Gabapentin increased mechanical pain thresholds but did not affect mechanical pain intensity nor other sensory variables [60]. Two studies evaluated the effects of hyperbaric oxygen treatment on secondary hyperalgesia immediately post-CBI using almost identical experimental designs [41,64]. Both studies found that hyperbaric oxygen treatment reduced the SHA when compared to ambient pressure [41,64]. Interestingly, the sequences starting with hyperbaric oxygen, conditioned the response in the subsequent ambient pressure test day (serving as a control), generating a similar reduction in SHAs. Riluzole (glutamate receptor antagonist) [10], melatonin [1], μ-opioid receptor antagonists [6], and local cooling of the CBI [59] had no clear effect on mechanical or thermal hyperalgesia [1,6,10,59,60], nor on other inflammatory variables [1,59].

Methodological studies. Repeatability: Within-day comparisons using the CBI-model (420 s at 47°C, 12.5 cm²) revealed that a 20% difference could be detected for all variables in a crossover design with twelve subjects (α = 0.05, β = 0.20), except for cool detection threshold and heat pain response at 43°C (see S1 Table for statistical definitions) [33]. On each day, the CBI produced robust hyperalgesia throughout the 6 h study period. Between-day comparisons revealed that the intra-individual, between-days coefficients of variation ranged from 9 to 36% for all sensory assessments along with erythema, except for the heat pain response to 43°C, and the brush-evoked allodynia, both showing a low reproducibility. These two variables were recommended to omit in between-day comparison studies [33]. A study using a comparable CBI-model (420 s at 47°C, 9 cm²) observed a correlation between test-retest of pain intensity scores following CBIs (r² = 0.44; P < 0.05) [27]. A study categorized as an intervention study, tested reliability (intraclass correlation coefficient [ICC]), and variability of areas of flare, secondary hyperalgesia, and allodynia using a relatively milder CBI-model (330 s at 45°C, 0.3 cm²) [28]. The authors concluded that the model was reliable in an investigator independent manner, although primary hyperalgesia outcomes were not addressed. The testing was performed 15 min post-CBI, consequently only addressing the reproducibility of the hyperalgesic response at a limited time span after the CBI.

Validation: The induction of a CBI produced long-lasting hyperalgesia, with primary hyperalgesia lasting between 24–48 h and secondary hyperalgesia remaining until 24 h post-CBI (300 s at 49°C, 3.75 cm²) [23]. One test-retest study evaluated the performance of different punctate stimulators for the assessment of SHAs [44]. The delineation of SHAs with nylon filaments and weighted-pin instruments were highly correlated with the application pressure. The weighted-pin instrument applying a high pressure (10,424 kPa) showed the greatest inter-observer reliability following a CBI [44].

A comparison of the CBI-model to other cutaneous heat pain models can be found in S3 File.

Physiological studies. A functional magnetic resonance imaging (fMRI) study found that high-sensitizers, i.e., subjects with large SHAs, had less activation of the default mode network (precuneus, posterior cingulate cortex) during noxious punctate mechanical stimulation post-CBI compared to low-sensitizers, i.e., subjects with smaller SHAs. Further, an inverse relationship between the magnitude of SHA and the volume of the caudate nucleus was found [2]. A twin-study including 51 monozygotic and 47 dizygotic twin pairs found that the SHA, area of brush-evoked allodynia, HPT, and pain during the CBI all had statistically significant heritable components. However, neither shared genetics nor environmental factors could explain the extent of CBI-induced heat hypersensitivity (ΔHPT [pre- vs. post-CBI]) [28].

Predictive studies. In patients undergoing elective arthroscopic anterior cruciate ligament repair, pain during a preoperative CBI significantly correlated with self-reported dynamic pain on postoperative days 0 to 2 (r = 0.65; P < 0.01) and days 3 to 10 (r = 0.57; P < 0.01) and resting pain ratings on postoperative days 0 to 2 (r = 0.60; P < 0.01) and days 3 to 10 (r = 0.59; P < 0.01) [56]. Other QST-variables such as thermal thresholds, mechanical thresholds, and SHA displayed a relatively weaker predictive value. A later high-powered study investigated the ability of a phasic (5 s) vis-á-vis a tonic (420 s) heat stimulus to predict postoperative pain, using identical stimulus areas (12.5 cm²) and temperatures (47°C) after total knee arthroplasty [18]. The authors found a significant, but very weak, correlation between postoperative VAS during walking on days 1 to 7, and, the phasic (r = 0.25; P = 0.02) and tonic (r = 0.27; P = 0.01) heating paradigms, respectively, deeming these variables clinically irrelevant predictors. Further, arthroscopic knee surgery did not alter postoperative hyperalgesic responses to CBIs when compared to the baseline preoperative responses [57].

Discussion

Short summary

The present review, including 64 studies, indicates that the contact burn injury model is a reference model in human experimental pain research. However, our data demonstrate first, a surprising lack of methodological standardization, despite the limited number of research groups employing the CBI-model in pain research. Second, although the model consistently provides long-lasting primary and secondary hyperalgesia, the reproducibility of the sensitizing responses of the model has only been validated in three studies [28,33,90]. Third, the evidence for using the tonic CBI-stimulus to predict acute post-surgical pain is weak [18,56]. Fourth, the pharmacological intervention studies with anti-inflammatory drugs, e.g., NSAIDs and glucocorticoids, have mostly been negative, which is perplexing, since the CBI is considered an inflammatory model. Fifth, while anti-hyperalgesic effects have been demonstrated for ketamine and to some extent also for adenosine, local anesthetics, and opioids, administered following the CBI, no single pharmacological intervention has been showing a consistent efficacy in reversing CBI-induced hyperalgesia.

Main contact burn injury model variables

Paradigms and thermode handling

The included studies reveal substantial variations in the applied heating paradigms (Table 2). Although the relationship between exposure time and temperature of a burn injury is established (Fig 2) [72], the time-course of hyperalgesia has only been investigated in a few studies, and thus different heating paradigms have not been compared. The heating paradigm of 420 s at 47°C is, however, the most commonly applied [1,2,5,6,10,12–16,18,20,21,27,29,32–34,36–39,41–44,46,48–50,53,55–62]. Reproducibility has been investigated for this heating paradigm [33], hyperalgesia is long-lasting [33] and adverse events are minor and infrequent (reported in 10/39 studies) [29,32–34,36,39,42,46,49,60].

None of the included studies have investigated the effects of changing the active thermode areas. The SHA has been observed to increase proportionally with the CBI-area (preliminary observations by the authors). Interestingly, a study attempting to replicate the heat/capsaicin model with a smaller thermode than previously reported (9 cm² vs. 12.5–15.7 cm²) [70,73] found that the smaller thermode was not able to produce stable SHAs, and, further, could not show an effect of gabapentin, as previously reported [91]. Similarly, another study could not find an effect of pre- and post-conditioning on heat sensory outcomes in the heat/capsaicin model [61]. These authors also used a smaller thermode during rekindling (3.75 cm²) compared to previous studies [70,73]. The findings indicate that changes in the contact thermode area probably may affect the degree of hyperalgesia and the pharmacological sensitivity of the CBI-method.

Contact thermode application pressures were reported in 34/64 of the included studies, utilizing a wide range of pressures. Interestingly, one study investigated the effect on thermal thresholds of varying application pressures (0.32–10 N) using an active thermode area of 9 cm² [92]. The authors concluded that altering the application pressure did neither affect the thermal thresholds nor affect the intra- or inter-subject reproducibility. However, these data only comprised phasic stimuli, not the tonic CBI-stimulus.

Induction site

Differences in sensitivity may occur between different skin sites as normal skin on the volar forearm was significantly more sensitive than the medial calf based on thermal detection thresholds [33] and mechanical pain thresholds [93], although conflicting results were found for heat pain thresholds [33,93].

Repeated CBIs on an ipsilateral, homologous skin site have been observed to induce habituation effects across sessions, e.g., decreased SHAs and increased heat pain thresholds in the second session [33,38,42,64]. This problem may be mitigated by using block-randomization and cross-over designs, thereby evenly dividing active drugs and placebo between sessions.

Validity and reproducibility of contact burn injury variables

Pathophysiological changes

As previously reported, Moritz and Henriques described first-degree burn injuries ranging from transient hyperemia to prolonged erythema with the formation of small vesicles [72]. Erythema reflects vascular changes in the burn area, and the degree of redness is measured by skin reflectance spectrophotometry [94]. The duration of erythema has varied substantially across CBI-studies. Other indices of inflammation, i.e., increased dermal blood flow, a rise in skin temperature, and flare, are only short-lasting phenomena post-CBI [46,61,95–97]. Increased dermal thickness as an index of skin edema, measured by high-frequency ultrasound technique, has only been applied in a limited number of studies, but seem to persist several hours post-CBI [1,64]. Interestingly, none of the included studies reported any significant effect on the classic inflammatory variables (edema, erythema, or temperature increase) by the drugs tested.

Assessing the central anti-hyperalgesic effect, by evaluating changes in SHA, is an essential outcome of many analgesic studies. The SHA is delineated via punctate stimulation with a nylon filament or a weighted-pin instrument. The CBI induces rather consistent secondary hyperalgesia, with a duration of 24 h. Interestingly, two studies have indicated that 12/100 (420 s at 47°C, 12.5 cm²) [42], and 10/64 (300 s at 46°C, 12.5 cm²) [19] of the subjects do not develop measurable SHAs. Paradoxically, QST assessments by themselves may induce secondary hyperalgesia [33,98].

Temporal summation, another measure of central sensitization, is generally facilitated in the CBI-model [47,48,53–55,62]. The temporal summation response appears modality-dependent due to the stimulation of different receptor subtypes [29,62]. Temporal summation has primarily been investigated in studies using ketamine and morphine, with the former usually providing a significant mitigating effect. However, other analgesics, e.g., dextromethorphan [99], imipramine [100], venlafaxine [101], and gabapentin [102], have been found to mitigate temporal summation, and could thus also be applied in the CBI-model.

General issues

Only a few studies have investigated test-retest reproducibility of the CBI-model variables, and when tested, the applied statistical methods have been inconsistent [27,28,33,44]. When calculating ICCs as a measurement of reliability, the between-subject variance and within-subject variance should preferably be reported, since the former may increase as a result of measurement heterogeneity on a group level, thereby artificially increasing ICCs [103]. However, the included studies did not provide this information [28,44]. An agreement test, presented as a Bland-Altman plot, has been recommended as a valid test-retest statistic mainly because of its detailed, transparent, and honest presentation of data distribution [103]. However, only one of the included studies presented this statistic, and the authors mainly focused on the inter-observer agreement [44]. One study claimed that there was a good test-retest reproducibility of pain scores during a CBI [27], but this was only based on a correlation coefficient between test-retest scores which is a suboptimal measure of reproducibility [103–105]. A review providing a post hoc analysis of test-retest data from a CBI-study found that SHAs were reproducible across multiple sessions. These calculations were based on ICCs, suggesting that subjects could be phenotyped according to the pattern of sensitization [42,90].

When assessing quantitative sensory thresholds, the subject’s reaction time, depending on nerve conduction velocity and cognitive-executive abilities, may influence the results. However, only a few of the included studies reported reaction time tests [1,5,43]. Sensory tests applying the ‘method of limits’ are especially subjected to the influence of reaction time. The effect of analgesic drugs with potential sedative properties may increase response latency, erroneously leading to higher pain thresholds (‘pseudoanalgesia’) [43]. This is an underreported source of systematic bias.

The contact burn injury in pharmacodynamic research

None of the evaluated analgesics had a consistent pharmacodynamic profile of attenuating, either primary or secondary hyperalgesia. Further, a substantial number of studies received a low-quality score questioning the methodological quality of the studies (cf. Methodological limitations of the review). Ketamine administration, however, was associated with a reduction in SHA and temporal summation, thus clearly attenuating central sensitization phenomena [53–55]. The effects of ketamine on primary mechanical hyperalgesia were more pronounced than on primary thermal hyperalgesia, which may be explained by potentially different mechanisms for mechanical and thermal hyperalgesia [34].

The administration of ibuprofen was associated with a reduction in motor brush-evoked pain response in the SHA following a CBI [39]. An fMRI study found that ibuprofen only induced cerebral blood flow changes during ongoing postoperative pain, not evidenced in pain-free subjects [106]. The results from the NSAID studies indicate that the effects are primarily centrally mediated but that relatively large doses are needed to reveal this effect [51]. Likewise, the one study that demonstrated an effect of glucocorticoids on SHAs [51] applied a larger, supra-physiological dose than used in previous studies [58]. The central effect of this large dose of glucocorticoid was rapid, thus likely not solely dependent on translational mechanisms. Interestingly, the studies evaluating anti-inflammatory drugs, i.e., NSAIDs and glucocorticoids, have mostly been negative but have received varying quality scores, raising the question of whether the results are correlated with the quality of the study. However, of the six studies evaluating NSAIDs, three different drugs and four different routes of administration were used along with several different outcome measures, obstructing a valid comparison between the studies. Further, among the three high-quality studies, only one study could be considered yielding a positive outcome [51], thus not changing the general conclusion of this review.

Regarding opioids, experimental pain models that apply deep tonic stimulations, thus primarily activating C-fibers, have been found to be more sensitive to systemic morphine than superficial phasic stimulations [107]. Compellingly, opioids reduce pain scores during a CBI [43], indicating that nociceptive transmission is at least partially C-fiber mediated.

Interestingly, although gabapentin only just significantly increased post-CBI mechanical pain thresholds [60], the number of clinical studies investigating this drug increased markedly in the following decades [108]. This exemplifies the use of the CBI-model as a translational model from experimental to clinical research.

The contact burn injury in clinical predictive studies

The potential for the CBI, applied as a test stimulus or a conditioning stimulus, in predicting acute postoperative pain, has been a matter of debate [18,56]. These discrepancies are likely due to the investigation of different surgical procedures (arthroscopic knee surgery vs. total knee arthroplasty), different test-sites (calf vs. thigh), and that a majority of patients in the negative study presented with preoperative pain [18]. Further, a type I error may have occurred in the hypothesis-generating study [56] since the negative follow-up [18] study included nearly five times as many patients than the positive study.

Methodological limitations of the review

The methodological quality of the intervention studies, assessed by the Oxford Quality Scoring System [109], was generally fairly low with a median (IQR) value of 2 (2–3). The Oxford Quality Scoring System was chosen over more sophisticated tools (e.g., Cochrane Collaboration’s tool for assessing the risk of bias), first, in awareness of the studies varying bibliographical age, and second, because it displays a high interrater validity [109]. Intervention studies were evaluated regardless of their quality score. The quality score depends on the information available in the reports, and journal requirements for trial reporting have not always been as comprehensive as today [109]. Furthermore, the scoring systems used in systematic reviews and meta-analyses, albeit important, only characterize certain aspects of the research design [110,111]. The quality scorings, therefore, may be difficult to interpret in a review, including studies of different time epochs. Thus, the individual studies may have been performed well regarding the somatosensory testing methodology, the main objective of the present review, nevertheless, receiving a low-quality rating. Valuable methodological information could have been neglected by excluding studies based on quality scores. Attempts were made at performing a quality scoring of the non-interventional studies. Incorporating study quality could provide clarity in studies presenting with contrasting results. Two potential scoring systems were considered: the GRADE tool [112,113] and the “checklist for the assessment of the methodological quality” [114]. However, due to considerable heterogeneity across the studies regarding methodology, outcome variables, and statistical processing, the authors decided to abandon the attempt to make a relevant quality scoring.

Another essential point is that the included studies demonstrated a high heterogeneity regarding the methodology of the CBI-model and associated outcome assessments. Consequently, a statistical meta-analysis of the included results was not deemed feasible and was not within the scope of this review.

When evaluating the effects of analgesics, and especially when comparing several analgesics, it is important to study the dose-response relationship [115]. However, only 20% of the pharmacodynamic studies used more than one drug dose, precluding examination of dose-response relationships.

Essential elements in future research

The heating area as an important variable

While the exposure time and the contact thermode temperature are well-known critical variables in the thermal energy transfer, the size of the heating area has not been systematically examined. The active thermode area governs the intensity of pain during CBI-induction and the primary hyperalgesia area, but also likely influences the magnitude of the SHA, the duration of secondary hyperalgesia, and sensory perception within the hyperalgesia areas. Hypothetically, these spatial characteristics may affect the pharmacodynamic effects of relevant analgesics.

The contact burn injury as an inflammatory model

The CBI is a surrogate, experimental model of inflammatory pain, and therefore demonstrates certain limitations compared to clinical pain. Although the model involves the cardinal signs of inflammation, i.e., edema, erythema, local hyperthermia, and evoked pain, the pharmacological sensitivity to anti-inflammatory analgesics, NSAIDs, and glucocorticoids, is ambiguous. The model lacks the spontaneous pain component usually present in acute clinical inflammatory states. A hypothetical explanation is that the area of the skin injury, corresponding to 0.06% of the body surface area, only activates a limited part of the mesencephalic-subcortical pain network. The limited nociceptive drive likely affects the response to relevant analgesics. Obviously, augmenting the extent of thermal injury by increasing the exposure time and/or the contact thermode area/temperature would lead to a second-degree CBI at the undesirable cost of irreversible skin damages. However, the inflammatory response could instead be augmented synergistically by topical administration of pro-inflammatory agents such as mustard oil [116], sodium lauryl sulfate [117], or the well-investigated capsaicin [73], enhancing the primary and secondary hyperalgesia components.

Characterization of phenotypes

As previously mentioned, phenotyping based on the SHA is possible across individuals [90]. These phenotypes are characterized by differences in brain structure and function [2], with ‘high-sensitizers’ presenting similar brain activation patterns to chronic pain patients [2]. Phenotyping based on a subject’s ‘sensitization’ pattern assessed by QST provides a potential for predicting the pharmacodynamic response to analgesics [118–120].

Conclusion

First, the present review revealed a large heterogeneity in the applied methodologies across the use of the CBI-model. It is well-known how the exposure time and temperature influence the degree of the cutaneous injury (Fig 2). However, another principal variable governing the heat energy transfer, the active area of the contact thermode, has not been systematically examined. Second, the pharmacodynamic sensitivity of the CBI-model suggests that the paradigm still needs to be optimized. The model shows robust analgesic efficacy for ketamine, but generally lacks sensitivity for anti-inflammatory drugs, contradicting the epithet that the CBI is an inflammatory pain model. Third, the evidence base for an optimal CBI-model is inadequate. However, standardization of the model is needed, and consequently, this review has provided suggestions for future use of the model (Table 4).

Table 4. Suggestions to consider when designing a CBI-model trial.

CBI-methodology
    1) Equipment calibration
    2) Heating paradigm: 420 s at 47.0°C; ≥ 9 cm²
    3) Induction site: lower arm or leg
Outcome assessments
    4) Pain during the CBI
    5) Primary hyperalgesia
    • Mechanical/thermal thresholds
    • Mechanical/thermal suprathreshold stimuli
    • Temporal summation
    6) Secondary hyperalgesia
    • Mechanical delineation of SHAs
    • Temporal summation
    7) Inflammatory variables
    • Erythema
    • Edema
Pharmacodynamic considerations
    8) Measurement of subjects’ reaction times (‘method of limits’)
    9) Use suitable dose-response designs
Statistical considerations
    10) Consider obtaining test-retest data

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Authors’ considerations, based on the review, when designing a contact burn injury (CBI)-model trial. 1) Calibration of the CBI-equipment is mandatory. 2) The most commonly used heating paradigm (the most commonly used heating area was 12.5 cm²). 3) The induction sites are the most frequently used. 4) CBI-induced pain can be used both as conditioning- and test-stimulus. 5) In the CBI-area assessment of thresholds, pain perception to suprathreshold stimuli or temporal summation can be used. 6) The secondary hyperalgesia area (SHA) is delineated by mechanical stimuli [44], and perception to temporal summation can be evaluated as central sensitization measures. 7) CBI-induced inflammatory variables to be considered are erythema and edema [1]. 8) Analgesic trials, using the ‘method of limits’ in threshold assessments, may require assessment of the subjects’ reaction times in order to avoid ‘pseudo-analgesia’ [43]. 9) Dose-response studies require a design with multiple doses [115]. 10) In order to validate the study methodology, a test-retest set-up should be considered [103].

Supporting information

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

Click here for additional data file.^{(30.4KB, docx)}

S1 Table. Statistical definitions.

(DOCX)

Click here for additional data file.^{(23.5KB, docx)}

S1 File. Embase search terms.

(DOCX)

Click here for additional data file.^{(20.4KB, docx)}

S2 File. Results from the miscellaneous studies.

(DOCX)

Click here for additional data file.^{(18.8KB, docx)}

S3 File. The contact burn injury model in comparison to other cutaneous heat pain models.

(DOCX)

Click here for additional data file.^{(42.1KB, docx)}

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author Caitlin R. Wessel received financial support by The National Institutes of Health (NIH) grant number NIHR01DA37621 to Bradley K. Taylor.’

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PLoS One. doi: 10.1371/journal.pone.0254790.r001

Decision Letter 0

John Kramer

19 Feb 2021

PONE-D-20-38717

Methodology and applicability of the human contact burn injury model: A systematic review

PLOS ONE

Dear Dr. Springborg,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 05 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

John Kramer

Academic Editor

PLOS ONE

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Additional Editor Comments:

Thank you for submitting your manuscript to PLOS ONE. The comments from the reviewers are attached. Overall, the manuscript has potential to serve as a valuable resource for researchers interested in the contact burn injury model of inducing primary and secondary hyperalgesia. My primary concern, however, is that the manuscript is burdened by redundancies, which makes it rather overwhelming to read and interpret. I would ask that the authors consider the comments of the reviewers and in turn attempt to streamline the results section accordingly, condensing where possible.

In addition, I would request that the authors confirm they searched for previously published systematic reviews/meta-analyses on the topic of contact burn injuries. This needs to be done to avoid duplicate efforts and multiple reviews written needlessly on the same topic. If there are none, please indicate as such in the manuscript. Finally, please consider using the AMSTAR tool to evaluate your systematic review and ensure it meets the highest methodological standard.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript provides a very thorough overview and summary of the contact burn injury model. The background section of the introduction is well written and succinct, however following sections providing additional background are lengthy and could be condensed and incorporated into the introduction, methods, and discussion. The methods are well written, however, substantially more information is needed on the quality assessment of articles. The results are rather repetitive, and the discussion is lengthy, and could be condensed. My main concern with the manuscript is the lack of removal of low-quality intervention studies. It is unclear to what end the author’s main findings are derived from low quality studies compared to high quality. I would suggest incorporating a more critical assessment of the literature throughout the discussion.

Specific comments attached separately.

Reviewer #2: This systematic review by Springborg and colleagues aimed to synthesize data from studies using human burn injury models. This is an important work and, for the most part, provides a nice overview of many human model parameters as applied in the literature. It is very comprehensive, which introduces some difficulties in reporting clear, concise and synthesized results due to obvious variation between studies.

I only have a few comments:

Page 12, line 125: "QST…….by application of graded chemical, electrical,…." What chemical and electrical stimuli are the authors referring to? To the reviewer`s knowledge, classical QST protocols do not employ such stimuli.

I would like to commend the authors on their consistent use of terminology, as they are certainly well aware of the ongoing controversy regarding 'central sensitization' being used as a broad term in human studies in contrast to the very well-defined neuronal construct in basic animal studies. I am glad to see that the psychophysical terminology was used and distinctions between primary and secondary hyperalgesia were made appropriately. This was especially important for the interventional trials as some drugs will affect the primary input and the 2HA, respectively.

However, with respect to the "timing of intervention" it would be interesting to know if the studies aimed at investigating whether the drugs affected the induction of hyperalgesia or lead to a reversal of an already established state of hyperalgesia? In my personal opinion, only the former would constitute a true "anti-hyperalgesic effect". The latter could just be called "analgesic effect" considering CBI as a human surrogate pain model.

In table 6 the use of "assessments of central mechanisms" is recommended. These tests are merely listed in the outcomes section in the introduction.

Please explain the methods/paradigms in a bit more detail, especially with regard to what mechanisms are potentially investigated with the respective paradigms.

Thank you.

**********

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Reviewer #1: No

Reviewer #2: No

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Attachment

Submitted filename: PONE-D-20-38717_Comments_Authors.pdf

Click here for additional data file.^{(52.8KB, pdf)}

PLoS One. 2021 Jul 30;16(7):e0254790. doi: 10.1371/journal.pone.0254790.r002

Author response to Decision Letter 0

4 Apr 2021

Below you will find a condensed answer to the requested corrections from the Reviewers. A complete response to the Editor and Reviewers' queries can be found in the 'Response to Reviewers' letter.

COMMENTS TO THE REVIEWERS

The authors acknowledge with gratitude the Reviewers’ effort in preparing the evaluation of the manuscript. The authors consider the suggestions and queries for having improved the manuscript significantly. The authors are very grateful to the Reviewers.

REVIEWER #1:

The authors thank the Reviewer for these positive comments. We have rewritten the Introduction and, as suggested, incorporated the additional background information in other sections. Further, we have provided additional information on quality assessment in the Material and method section. The Result and Discussion sections have been abridged substantially, i.e., 17% and 22%, respectively. The authors have put a great deal of effort into shortening the sections without losing the sense of coherence.

COMMENTS:

Q1: Line 40-44: The first sentence required 64 references, yet the second and, more informative sentence, remains unreferenced?

R1: The in-text references #1-64, comprising all the studies of the present review, were actually a technical feature facilitating a chronological order of the study material from the beginning. In the second sentence of the paragraph, three references have been added (Page 3, Line 42-44).

Q2: Sections “Classification of cutaneous burns”, “Contact burn injury method”, and “Evaluation of contact burn injury-induced changes” are all rather lengthy and feel disjointed between the introduction and the methods. Consider condensing these sections to incorporating them into the discussion, such that following the purpose of the review, the manuscript leads seamlessly into the methods.

R2: We agree that the subsections in the Introduction section could be incorporated elsewhere. We now have a single conjoined Introduction.

The rest of the information in the mentioned sections has been condensed and added in the Discussion.

Q3: With numerous acronyms, consider removing SHA. Numerous times throughout the manuscript, secondary hyperalgesia is mentioned but not short formed, while SHA is short formed. This feels rather odd when reading.

R3: The authors agree that it is inconsequential to switch between ‘secondary hyperalgesia area’ and ‘SHA’. However, since ‘SHA’ is mentioned numerous times (41 in the main text of the revised manuscript), we have changed ‘secondary hyperalgesia area’ to ‘SHA’ in all relevant places. There is, however, a distinction between ‘secondary hyperalgesia’ and ‘secondary hyperalgesia area’, and in order to improve readability, the authors have kept ‘secondary hyperalgesia’ unabbreviated.

Q4: Line 208-210. 73 records assessed for eligibility, 12 excluded, 5 added, to total 64 does not add up. (73-12+5=66)

R4: The authors thank the Reviewer for pointing out this error. We excluded 14 studies and not 12. This has been changed now.

Q5: The authors do not discuss their quality assessment until the limitations section of the review. Why are these not further discussed in greater detail throughout the manuscript?

R5: Thank you for raising a relevant objection. Quality assessment using the Oxford Quality Scoring System can only be performed on RCTs. Therefore, quality assessment scores have only been made for the intervention studies and are thus only relevant when discussing these studies. However, we agree that more information could be provided about the quality scores. Consequently, the authors have put more effort into discussing quality scoring throughout the manuscript and have added additional information about quality scoring in the limitations sub-section.

Q6: The methods do not provide enough detail to interpret the quality outcomes (i.e. what does a score of 2 mean?). To that end, authors suggest over half of the intervention studies received a score of 0 on their chosen scale. What does a score of 0 represent? The authors have not provided information to interpret these values given in their tables. Additionally, this scale is more lenient than Cochrane’s suggested tool. Why were so many studies with quality such low quality included in the review and the discussion? The justification that “most were hypothesis driven pragmatic studies” does not accommodate for both methodological quality or author bias. This needs to be better addressed in the results and discussion.

R6: The authors thank the Reviewer for these suggestions. We have added additional information in the method section about the interpretation of the quality scores (please, also cf. R5 above).

During the revision of the manuscript, the authors became aware of an erroneous scoring procedure of the papers. The Oxford Quality Scoring System evaluates information about randomization, blinding, and subject dropouts. Studies get subtraction of a point if the randomization process and/or the blinding process was described and was inadequate. However, in our initial scoring of the studies, we subtracted a point if the information was missing. This resulted in a lot of studies receiving a score of 0 even though they were described as randomized, double-blind studies. We believe this may have given an inaccurate picture of the quality of the studies. The quality scores have, thus, been updated.

As mentioned in R5, we have updated the discussion regarding the quality scores and the inclusion of low-quality studies. We believe that valuable information on methodological aspects of the somatosensory testing would potentially have been lost by excluding intervention studies based on quality scores.

Q7: I’m curious as to why the authors did not perform any meta-analysis of findings? With the high number of included studies, it would have been beneficial for some of the more common outcomes to be included in separate meta analyses.

R7: In order to perform a meta-analysis, the authors would have had to look at a number of studies employing the same intervention and using identical somatosensory testing methodology. However, given the heterogeneity of the CBI methodologies applied, we did not find it meaningful to perform a meta-analysis.

Q8: Line 785 – what about capsaicin as well? The heat capsaicin model is very well documented.

R8: The Reviewer can rightfully claim that the authors could have mentioned the well documented heat-capsaicin model here. We have changed the sentence now.

Q9: Table 6 – These seem to be rather vague recommendations for future studies. Specifically, how long should stimulus be applied? To what temperature? These details would be expected in a summary table outlining the updated recommended methodology, as alluded to in the abstract.

R9: We agree with the Reviewer. The information in Table 4 has now been condensed, providing the most relevant methodological information available (Page 50-51).

REVIEWER #2

The authors thank the Reviewer for the positive comments. We have made an effort to abridge and streamline the manuscript further.

COMMENTS:

Q1: Page 12, line 125: "QST…….by application of graded chemical, electrical,…." What chemical and electrical stimuli are the authors referring to? To the reviewer`s knowledge, classical QST protocols do not employ such stimuli.

R1: The authors acknowledge that ‘classic’ QST-assessments mainly involve thermal or mechanical stimulations. However, several studies, including some studies from the current review, employ electrical stimuli or chemical stimuli. See 'Response to Reviewers. Letter for references.

Q2: I would like to commend the authors on their consistent use of terminology, as they are certainly well aware of the ongoing controversy regarding 'central sensitization' being used as a broad term in human studies in contrast to the very well-defined neuronal construct in basic animal studies. I am glad to see that the psychophysical terminology was used and distinctions between primary and secondary hyperalgesia were made appropriately. This was especially important for the interventional trials as some drugs will affect the primary input and the 2HA, respectively.

R2: Thank you very much for the relevant question. The authors agree that the timing of the intervention is an important factor potentially affecting the attenuation of hyperalgesia. The timing of interventions has indeed already been indicated for the individual studies in Table 3, as well as in the ‘Study outcomes – Intervention studies’ sub-section in the Results.

Q3: In table 6 the use of "assessments of central mechanisms" is recommended. These tests are merely listed in the outcomes section in the introduction.

Please explain the methods/paradigms in a bit more detail, especially with regard to what mechanisms are potentially investigated with the respective paradigms.

R3: The assessments of central mechanisms refer predominantly to an evaluation of the development of secondary hyperalgesia and to a change in the response to temporal summation. Describing the specific QST outcomes is not within the scope of this review, and we refer to additional literature on this subject. However, the results regarding secondary hyperalgesia and temporal summation have been described throughout the manuscript. As mentioned in R9 (Reviewer #1) we have updated Table 6 (now Table 4) and condensed the information to only include the most important methodological information.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(100.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0254790.r003

Decision Letter 1

John Kramer

11 May 2021

PONE-D-20-38717R1

Methodology and applicability of the human contact burn injury model: A systematic review

PLOS ONE

Dear Dr. Springborg,

Review 2 has made a number of important suggestions, which the authors should consider. There is a need to consider the effect of heterogeneity between studies and the impact this has on the overall interpretation, as well as update to current standards. I am hopeful that, with a fair response to these comments, the manuscript will be satisfactory and ready for publication.

Please submit your revised manuscript by Jun 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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We look forward to receiving your revised manuscript.

Kind regards,

John Kramer

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have substantially improved the manuscript through the revision process. Many redundancies have been removed, improving the readability of the manuscript. The majority of my comments have been adequately addressed. I have a few minor comments for the authors consideration. The first should be very easy to include, and the remaining two may be worth consideration (or perhaps authors already considered this and sought not to include as it did not improve the interpretation).

PRISMA Diagram and checklist. These are the old versions of the PRISMA diagram and checklist. These were both updated in 2020. Consider updated to keep in line with PRISMA guidelines.

I previously suggested authors further discuss their quality assessment. Following revisions, the authors have pointed out that only intervention studies were assessed for quality. Are there no available tools to assess article quality for non-intervention studies? To that end, while the quality of intervention studies has been assessed, do the authors believe there would be any value in also using a tool to evaluate the quality of the data/findings from each study (using the GRADE tool perhaps)?

Throughout the results and discussion, there is clearly much heterogeneity in study findings. The general sense from the review is there is still “much work to do” in terms of using this model. An example of this would be the perplexing findings of the non-responsiveness of the model to anti-inflammatory drugs, despite being an inflammatory model. One avenue to address these concerns may be in weighing the quality of findings (in terms of Oxford and GRADE tools) to reach some more definitive conclusions. As it stands now, the quality assessment for the most part appears to be for the reader’s information, rather than directly used to help guide the synthesis of findings. It would be interesting to see if incorporating study quality alongside such contrasting findings could provide some clarity in such circumstances.

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS One. 2021 Jul 30;16(7):e0254790. doi: 10.1371/journal.pone.0254790.r004

Author response to Decision Letter 1

10 Jun 2021

B. COMMENTS TO THE REVIEWERS

REVIEWER #1:

The authors thank the reviewer for the kind comments and the help in improving the manuscript.

Q1: PRISMA Diagram and checklist. These are the old versions of the PRISMA diagram and checklist. These were both updated in 2020. Consider updated to keep in line with PRISMA guidelines.

R1: The authors acknowledge the reviewer for pointing this out. The updated versions of the PRISMA diagram and checklist from 2020 have been attached to the submission.

Q2: I previously suggested authors further discuss their quality assessment. Following revisions, the authors have pointed out that only intervention studies were assessed for quality. Are there no available tools to assess article quality for non-intervention studies? To that end, while the quality of intervention studies has been assessed, do the authors believe there would be any value in also using a tool to evaluate the quality of the data/findings from each study (using the GRADE tool perhaps)?

R2: There are several tools for assessing the quality of non-randomized studies. However, the authors have not been able to find a single tool that would be able to assess the quality of all the non-intervention studies in an intelligible fashion due to the considerable heterogeneity among these studies. Thus, the following sentence has been added to the Discussion:

- Page 48, Line 627-633: ‘Attempts were made at performing a quality scoring of the non-interventional studies. Incorporating study quality could provide clarity in studies presenting with contrasting results. Two potential scoring systems were considered: the GRADE tool [1,2] and the “checklist for the assessment of the methodological quality” [3]. However, due to considerable heterogeneity across the studies regarding methodology, outcome variables, and statistical processing, the authors decided to abandon the attempt to make a relevant quality scoring.’

Q3: Throughout the results and discussion, there is clearly much heterogeneity in study findings. The general sense from the review is there is still “much work to do” in terms of using this model. An example of this would be the perplexing findings of the non-responsiveness of the model to anti-inflammatory drugs, despite being an inflammatory model. One avenue to address these concerns may be in weighing the quality of findings (in terms of Oxford and GRADE tools) to reach some more definitive conclusions. As it stands now, the quality assessment for the most part appears to be for the reader’s information, rather than directly used to help guide the synthesis of findings. It would be interesting to see if incorporating study quality alongside such contrasting findings could provide some clarity in such circumstances.

R3: The authors agree that it might be interesting to review the different studies in light of their quality scores. However, there are still relatively few studies evaluating each drug group, and these studies use a very different methodology in terms of administration routes, outcome measures, etc. When reviewing each drug group, the general conclusion does not seem to change when only the high-quality studies are included (Oxford quality score 3-5). Thus, the authors have added the following sentence to the Discussion:

- Page 46-47, Page 590-597: ‘Interestingly, the studies evaluating anti-inflammatory drugs, i.e., NSAIDs and glucocorticoids, have mostly been negative but have received varying quality scores, raising the question of whether the results are correlated with the quality of the study. However, of the six studies evaluating NSAIDs, three different drugs and four different routes of administration were used along with several different outcome measures, obstructing a valid comparison between the studies. Further, among the three high-quality studies, only one study could be considered yielding a positive outcome [4], thus not changing the general conclusion of this review.’

REFERENCES

1. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490. doi: 10.1136/bmj.328.7454.1490 [doi];328/7454/1490 [pii].

2. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6. doi: 336/7650/924 [pii];10.1136/bmj.39489.470347.AD [doi].

3. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-84. doi: 10.1136/jech.52.6.377. PubMed Central PMCID: PMCPMC1756728.

4. Stubhaug A, Romundstad L, Kaasa T, Breivik H. Methylprednisolone and ketorolac rapidly reduce hyperalgesia around a skin burn injury and increase pressure pain thresholds. Acta Anaesthesiol Scand. 2007;51(9):1138-46. doi: 10.1111/j.1399-6576.2007.01415.x.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(22.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0254790.r005

Decision Letter 2

John Kramer

6 Jul 2021

Methodology and applicability of the human contact burn injury model: A systematic review

PONE-D-20-38717R2

Dear Dr. Springborg,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

John Kramer

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Unclear to me why Figure 1 (PRISMA diagram) is referenced in the introduction. Please consider removing the "?" in Table 4.

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0254790.r006

Acceptance letter

John Kramer

21 Jul 2021

PONE-D-20-38717R2

Methodology and applicability of the human contact burn injury model: A systematic review

Dear Dr. Springborg:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. John Kramer

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

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S1 Table. Statistical definitions.

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S1 File. Embase search terms.

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S2 File. Results from the miscellaneous studies.

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S3 File. The contact burn injury model in comparison to other cutaneous heat pain models.

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Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Methodology and applicability of the human contact burn injury model: A systematic review

Anders Deichmann Springborg

Caitlin Rae Wessel

Lars Peter Kloster Andersen

Mads Utke Werner

Roles

Abstract

Introduction

Fig 1. PRISMA flow diagram for the search algorithm [68].

Fig 2. Time-temperature relationship of the contact burn injury.

Materials and methods

Eligibility criteria

Search strategy and selection

Categorization of studies

Data extraction and data analysis

Results

Literature search

Contact burn injury characteristics

Table 1. Contact burn injury characteristics.

Contact burn injury methodology

Post-burn changes

Study characteristics

Table 2. Study characteristics.

Intervention studies

Table 3. Intervention study results.

Study outcomes

Intervention studies

Discussion

Short summary

Main contact burn injury model variables

Paradigms and thermode handling

Induction site

Validity and reproducibility of contact burn injury variables

Pathophysiological changes

General issues

The contact burn injury in pharmacodynamic research

The contact burn injury in clinical predictive studies

Methodological limitations of the review

Essential elements in future research

The heating area as an important variable

The contact burn injury as an inflammatory model

Characterization of phenotypes

Conclusion

Table 4. Suggestions to consider when designing a CBI-model trial.

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

John Kramer

Roles

Author response to Decision Letter 0

Decision Letter 1

John Kramer

Roles

Author response to Decision Letter 1

Decision Letter 2

John Kramer

Roles

Acceptance letter

John Kramer

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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