Evaluation of Post-block Hypersensitivity Using Quantitative Sensory Testing Before, During, and After Axillary Brachial Plexus Block Resolution in Healthy Volunteers

Abstract

Background

The problem of a sharp increase in pain after resolution of a nerve block, known as rebound pain, has been increasingly recognized. It is currently unknown whether rebound pain simply reflects the unmasking of untreated, residual surgical pain, or if it represents a de novo hyperalgesic state driven by a mechanistic resetting of pain thresholds in response to regional anesthesia. In this study, we assessed nociceptive processing after a single-injection axillary brachial plexus block in healthy volunteers, to detect whether a previously blocked arm displayed objective hypersensitivity, in the absence of surgical pain.

Methods

Healthy volunteers received a single-injection axillary brachial plexus block using 15cc of mepivacaine 1.5%, with their contralateral unblocked arm serving as a control. Pain sensitivity between arms was compared using a range of Quantitative sensory testing (QST), comparing punctate, pressure and heat pain using paired t-tests or Wilcoxon sign-rank-tests. The primary outcome was heat pain threshold to 1/10 pain, compared between previously blocked and control arms at 60-minutes post-motor-resolution (MR), with secondary outcomes being other modalities compared at this timepoint. Additionally, we explored differences in maximally sensitized values during the entire post-block period.

Results

All 40 participants (age:19–64 years, 60% female) completed the study. At 60-minutes post-MR, heat pain threshold to 1/10 pain was not significantly different between arms (block:40.8±2.2°C, control:41.2±2.6°C; p=0.160). Testing of several other sensory modalities revealed only a slightly lower temperature to reach 5/10 heat pain in block versus control arm. When examining the maximally sensitized values including 3-hours after MR, the control arm showed greater sensitivity in some tested modalities (punctate pain threshold and painful after sensations), but not others (heat and pressure pain thresholds and tolerances, temporal summation of pain).

Conclusions

Multimodal pain testing revealed no evidence of general post-block hypersensitivity during resolution of a single-injection axillary brachial plexus block.

Summary Statement:

Evaluation of nociceptive sensitivity in the hours after axillary brachial plexus block resolution in 40 healthy volunteers revealed no evidence of increased sensitivity which could contribute to the phenomenon of rebound pain.

Introduction

Regional anesthesia is a powerful perioperative tool, serving as the primary anesthetic and/or part of a multimodal pain management strategy. Regional anesthesia has been shown to reduce acute and persistent postoperative pain, and opioid consumption.¹ However, 40–50% of patients experience acute worsening of pain upon the resolution of a single-injection nerve block.² This phenomenon, termed “rebound pain,”^3,4 typically lasts for 2–6 hours,⁵ and may be mitigated with additional multimodal analgesics, or largely prevented with a continuous nerve block catheter to prolong nerve block duration.⁵

One important mechanistic question is whether rebound pain reflects a true temporary resetting of the nociceptive system (hypersensitivity), or simply an unmasking of surgical pain as the nerve block wears off. However, distinguishing overt hypersensitivity secondary to a blocked state from a simple re-occurrence of postoperative pain is challenging in clinical settings, where surgical pain is present, and the trajectory of pain resolution varies among individuals.⁶

This study assessed nociceptive sensitivity in healthy volunteers across the entire time course of a single-injection axillary brachial plexus block, from careful assessment of baseline out to 3-hours after nerve block resolution. We investigated whether participants experienced heightened sensitivity to heat and pressure pain, or changes in central sensitization, in the absence of a surgical incision. The primary outcome was the difference in heat pain threshold at 60-minutes after full motor resolution, compared between the block and control arms. The null hypothesis was that no difference in sensitivity would be observed between block and control arms, consistent with the contention that rebound pain reflects the relatively sudden unmasking of surgical pain following nerve block resolution, rather than frank nociceptive sensitization.

Methods

Patient selection and recruitment

All procedures were approved by the Mass General Brigham IRB (Protocol#2023P001767), and registered at Clinicaltrials.gov (NCT06005480; PI: Yun-Yun K. Chen, registered August 22, 2023). Participants were recruited using online advertisements and underwent a video-based virtual informed consent process, with description and visualization of study equipment prior to enrollment. Electronic signature for informed consent was obtained through REDCap.^7,8 Inclusion criteria were English fluency, age 18–65 years old, and body mass index <35 kg/m². Exclusion criteria included history of local anesthetic allergy, neuropathy, loss of any limb, coagulopathy or bleeding disorders, alcohol or drug abuse, seizures, current acute or chronic pain, and skin/tissue infection affecting the upper extremities. Participants received financial compensation for participation in the study.

Baseline assessments

The study flow is depicted in Figure 1. Participants completed a survey of basic demographics including age, gender, race/ethnicity, and marital status, as well as baseline assessments of pain intensity and pain interference in the past week (Brief Pain Inventory, BPI),⁹ anxiety, depression, and sleep disturbance (PROMIS short forms),¹⁰ somatization (Brief Symptom Inventory, BSI),¹¹ pain catastrophizing (Pain Catastrophizing Scale, PCS),¹² and positive and negative affect (PANAS)¹³ using self-reported validated questionnaires. Next, participants underwent baseline quantitative sensory testing (QST), received an axillary brachial plexus block, and underwent repeated QST until 3-hours after full motor block resolution.

Figure 1. Study flow diagram.

Each round of Quantitative Sensory Testing (QST) included assessments of heat pain detection thresholds (1/10, 5/10, and 10/10 pain), touch and pain detection thresholds using von Frey monofilaments, suprathreshold punctate pain ratings using weighted pinprick stimulation, temporal summation of pain to pinprick train and painful aftersensations after that train, pain threshold and tolerance using handheld algometer at the forearm and trapezius, and cuff pressure pain threshold. For each round of QST (~20 minutes/round), the control arm was tested before the block arm. Each test modality was completed on both arms before moving on to the next modality. An approximate timing of each portion of the protocol is depicted on the right.

Nerve Block

All procedures were conducted in the Center for Clinical Investigation at Brigham and Women’s Hospital (Boston, MA), with two anesthesiologists present for the duration of nerve block placement and 30-minutes thereafter. Each participant served as their own control. The laterality of the arm receiving the nerve block (left or right) was randomized per participant using the randomization function in REDCap. Prior to nerve block placement, a 20-gauge intravenous catheter was placed in the antecubital fossa of the control arm and standard American Society of Anesthesiologist (ASA) monitors were applied. The axillary brachial plexus blocks were performed using sterile technique by a specialty-trained, experienced regional anesthesiologist (YKC, PL) with the support of a second regional anesthesiologist (KLS, SG) for verification and injection. After initial scanning using a linear transducer probe at the axilla (Sonosite X-Porte HFL50x, FUJIFILM Sonosite Inc., Bothell WA), the skin was anesthetized with 1ml of 1% lidocaine injected using a 25-gauge needle. Thereafter, a 22-gauge 5cm needle (SonoPlex II Facet, PAJUNK, City, Country) was advanced under ultrasound guidance to the musculocutaneous, radial, median and ulnar nerves. After negative aspiration for blood, 3–4ml of 1.5% mepivacaine was deposited around each nerve, with a maximum of 15 ml for the entire nerve block. The time of nerve block placement was recorded as the end of mepivacaine injection.

Motor and Sensory Evaluation

To monitor for onset and resolution of block, motor strength testing was performed on bilateral upper extremities before and after block using the Medical Research Council Manual Muscle Testing scale (0–5). We tested finger adduction and abduction, wrist flexion and extension, elbow flexion and extension, and grip strength. Sensory detection in different end nerve distributions was assessed using detection of cool sensation to alcohol swab application. Following block placement, motor and sensory function was tested every 2.5-minutes, until nerve block onset (0/5 strength in all nerve distributions), and loss of cool sensation to alcohol swabs occurred in end nerve distributions (median, ulnar, radial, musculocutaneous nerves). The time at which this occurred was recorded as “full nerve block onset.” Motor testing was performed every 10 minutes until motor function began to return in at least one distribution. Subsequently, motor and sensory testing was performed every 5 minutes until the patient had motor resolution (MR; 5/5 strength in all nerve distributions), and each 20-minutes thereafter for 3-hours.

Temperature assessments

Skin temperature of bilateral hands was measured using a continuous adhesive skin temperature probe attached to a vital signs monitor, recorded at baseline, and every 5 minutes through 3-hours post-MR.

Quantitative Sensory Testing of Pain

We used standardized QST tools to systematically assess various domains of nociceptive sensitivity, including heat pain (contact thermode), touch and punctate pain (von Frey monofilaments and weighted mechanical pinprick probes), pressure pain threshold and tolerance (hand-held algometer, and controlled cuff inflator).^14,15 The duration of each QST round was approximately 20-minutes, with each modality applied to both arms, control arm followed by the block arm, before proceeding to the next modality. A baseline round of QST was performed prior to nerve block administration. Subsequent QST rounds were performed after motor onset of the block and at 20-minute intervals after first signs of motor function returning until 3-hours after MR. Maximum stimulus limits were predefined for each QST modality to remain below the threshold for tissue damage.

Heat Pain Detection Thresholds:

Heat pain sensitivity was assessed using a contact thermode (3cm x 3cm), which delivered heat stimuli directly to skin, with temperature controlled using a laptop interface (Medoc Advanced Medical Systems, Ramat Yishai, Israel). Before testing, a grid was marked on the volar aspect of both the block and control forearms to ensure consistent and symmetric probe placement across repeated QST sessions. The thermode was secured to the forearm using a soft strap, with the probe temperature starting at a baseline of 35°C, and increasing at 2°C/second. Participants were instructed to press a button when the thermal stimulus first became painful (1/10 pain intensity), at which point the thermode temperature rapidly returned to baseline (35°C). This procedure was repeated 2 more times, with participants indicating when the thermal stimulus reached 5/10 and 10/10 pain levels, respectively, each followed by a return to 35°C. The maximum allowable temperature was set at 50°C to prevent tissue injury.

Touch and Punctate Pain Thresholds:

The detection threshold of touch and punctate pain was assessed using von Frey monofilaments (von Frey Semmes-Weinstein monofilaments, Stoelting, IL) of increasing diameters. Each monofilament exerted a calibrated, constant force on the skin, scaled logarithmically from size 1.65–6.65 (0.008 to 300g). Monofilaments were applied sequentially in order of increasing thickness to the 3^rd digit, with participant indicating the touch detection threshold, and subsequently, the pain threshold. If no pain was induced at the heaviest monofilament size, 6.65 was recorded as pain threshold.

Suprathreshold Punctate Pain Ratings:

To assess punctate pain, weighted pinprick probes were used (MRC Systems, Heidelberg, Germany). These consist of metal filaments, which are specially machined to feel sharp while not breaking or damaging skin, connected to free-floating weights (64, 128, 256, and 512 mN) within handheld metal cylinders. This allows the filament to be applied with a consistent force, when applied vertically to the skin. This was performed over the index finger between the two most distal joints. Subjects rated the intensity of pain elicited by each weighted filament using a 0–10 numerical rating scale (NRS).

Temporal Summation of Pain (TSP) and Painful After Sensations (PAS):

Using the lowest weight probe that elicited pain ratings of 2/10–4/10, a train of 10 stimuli was applied to the index finger at a frequency of 1 stimulus/second. Participants rated the pain intensity using a 0–10 NRS, rated at the 5^th and 10th stimulus. TSP was calculated as the difference between the pain rating for the tenth stimulus and the first stimulus. Participants also were asked to rate any lingering pain in the area of stimulation 15-seconds after the stimulus train, to assess for the presence and degree of PAS.

Pressure Pain Threshold and Tolerance:

Pressure pain threshold and tolerance were measured using a handheld pressure algometer (FPX50, Wagner Instruments, Greenwich, CT), which allows accurate measurement of pressure exerted in 0.5 cm² circular probe area. Pressure was applied over the forearm and trapezius, increasing gradually at approximately 1 lb/second (0.45 kg/second). Participants verbally indicated when the pressure first became painful (pressure pain threshold) and when it reached the maximum pain they could tolerate, at which point the tester stopped (pressure pain tolerance). The maximum applied pressure was limited to 20 lbs (9 kg) of force.

Cuff Pressure Threshold:

A Hokanson rapid inflation cuff (Hokanson, Inc., Bellevue, WA) was wrapped around the forearm, approximately 2 cm distal to the elbow crease, with placement marked prior to the first trial to ensure consistency across sessions. Pressure was increased at a rate of approximately 10–20 mmHg/second until the participant first reported pain (cuff pressure-pain threshold), at which point the pressure was instantaneously released. The maximum applied pressure was limited to 400 mmHg.

Statistical analysis

The predefined primary outcome was heat pain threshold, defined as the temperature at which participants reported 1/10 pain intensity, assessed at 60-minutes post-MR (T60) and compared between the control and block arms within the same participant. Within-participant differences between arms were assessed using a paired t-test for normally distributed data, or a Wilcoxon signed-rank test for non-normal data. This time point (T60) was selected due to its temporal proximity to sensory and motor resolution, as well as reported rebound pain, based on prior literature.^16,17

To account for variability in sensory block resolution and to more thoroughly investigate the time window during which hypersensitivity might occur, we also conducted an additional, un-prespecified analysis across the full 3-hour post–MR period. For each QST modality and arm, we identified the maximum deviation in the direction of increased sensitivity. Comparisons between the block and control arms were then performed using paired t-tests or Wilcoxon signed-rank tests, as appropriate, depending on normality (Shapiro–Wilk test).

Within-participant skin temperature differences between arms were also assessed using paired t-tests or Wilcoxon signed-rank tests.

All analyses were conducted in SPSS (ver.29, IBM Corp, Chicago, IL). Statistical significance was set at p<0.05. To estimate the required sample size for our primary analysis, we determined a priori that 40 participants would provide 80% power with a two-sided alpha of 0.05 for superiority testing using paired comparisons between the block and control arms. The calculation assumed a standard deviation of difference of 3.0°C, a minimum detectable difference of 1.4°C, and a minimum effect size of 0.467, based on prior data from healthy volunteers.¹⁵

Results

Participants’ (n=40) baseline demographics, psychological and pain characteristics are reported in Table 1. Participants’ median age was (29 years [24.0, 49.3]; range:19–64), body mass index 23.5 kg/m2 ([22.0, 26.0]; range:19.4–34.8), and 24 were females (60%). No participants had chronic pain. Baseline pain on BPI was very low (0 [0.0, 0.2], range:0–0.7, scale:0–10), with 19 participants scoring any pain. Pain interference was also low (0 [0.0, 3.8], range:0–67, scale:0–100). Pain catastrophizing scores demonstrated a range of values (5.5 [1.3, 13.5]; scale:0–52). The average group ratings for anxiety (t-score:50.8±2.7), depression (t-score:47.4±3.2), and sleep disturbance (t-score:48.2±2.7) were around population means (t-score of 50) and somatization scores were low (6.0 [6.00, 7.0], range:6–9; scale:6–30). Some small but significant differences in baseline QSTs were observed between control and block arms (Supplemental Table 1).

Table 1.

Demographics, pain and psychological characteristics (n=40)

Demographics	Mean±SD, Median [IQR], or n(%)	Range
Age (years; median [IQR])	29.0 [24.0, 49.3]	19 – 64
BMI (kg/m2; median [IQR])	23.5 [22.0, 26.0]	19.4 – 34.8
Sex (n, %)
Male	16 (40%)
Female	24 (60%)
Gender
Man	17 (42.5%)
Woman	22 (55%)
Transgender	1 (2.5%)
Race/ethnicity (n, %)
White	28 (70%)
Asian	5 (12.5%)
Hispanic/Latino	2 (5%)
Black/African American	1 (2.5%)
Other	4 (10%)
Marital status (n, %)
Married	4 (10%)
Single	30 (75%)
Divorced	2 (5%)
Living with partner	4 (10%)
Highest level of education
Some college	6 (15%)
College graduate	18 (45%)
Master’s degree	13 (32.5%)
Doctoral degree	3 (7.5%)
Diagnoses
Anxiety	7 (17.5%)
Depression	9 (22.5%)
Phobias	1 (2.5%)
OCD	1 (2.5%)
Alcohol use
None	20 (50%)
1–4 times per week	16 (40%)
5–10 times per week	3 (7.5%)
>20 times per week	1 (2.5%)
Tobacco use
Non-smoker	39 (97.5%)
Rarely	1 (2.5%)
Randomization to axillary brachial plexus block arm
Left arm	20 (50%)
Right arm	20 (50%)
Pain and psychological characteristics
BPI pain severity (range:0–10; median [IQR])	0 [0.0, 0.2]	0–0.7
BPI pain interference (range:0–100; median [IQR])	0 [0.0, 3.8]	0–67
Pain catastrophizing (PCS; range:0–52; median [IQR])	5.5 [1.3, 13.5]	0–34
Somatization (BSI; range:6–30; median [IQR])	6.0 [6.0, 7.0]	6–9
Anxiety (PROMIS; range:7–40; median [IQR])	13.0 [10.0, 16.8]	7–23
Depression (PROMIS; range:8–35; median [IQR])	10.0 [8.0, 15.5]	8–32
Sleep disturbance (PROMIS; range:8–40; mean±SD)	18.9±6.4	9–35
Negative affect (PANAS; range:10–50; median [IQR])	15.0 [11.0, 20.0]	10–34
Positive affect (PANAS; range:10–50; mean±SD)	33.8±6.3	19–47

Abbreviations: BMI, body mass index; BPI, Brief Pain Inventory; BSI, Brief Symptom Inventory; PANAS, Positive and Negative Affect Schedule; PCS, Pain Catastrophizing Scale; PROMIS, Patient-Reported Outcomes Measurement Information System; IQR, Interquartile Range [25, 75]

Nerve block onset and resolution

Axillary brachial plexus block placement was completed in 5.7±1.4 minutes (mean±SD). The time to total sensory loss after block placement was 18.1±12.8 minutes, and time to full motor block was 32.8±9.5 minutes. In a single round of QST after block onset, all participants felt no heat pain at 50°C (maximum allowed). QST rounds resumed after first signs of motor function return (movement in their fingers or elbow flexion), which was 86.4±29.5 minutes after nerve block placement, and were repeated thereafter every 20 minutes. Sensory function return was detected somewhat later than motor function return, with time to sensory return in any nerve distribution at 122.0±35.5 minutes. (Supplemental Figure 1). All participants had full return of motor and sensory to baseline function at the end of the study.

Time-course of changes in sensitivity and temperature

The time to full MR and sensory resolution for all nerve distributions was 196.9±38.9 and 215.1±40.1 minutes, respectively (difference:18.2±23.7 minutes). Figure 2 shows the time course of each QST modality at baseline, at nerve block onset, during nerve block resolution, and every 20 minutes after MR, for the block and control arms. There was a slight increase in pain sensitivity in the control arm, relative to its baseline, across most modalities.

Figure 2. Time-course of nociceptive sensitivity across multiple quantitative sensory tests before (baseline), during, and after axillary brachial plexus block.

Time 0 represents axillary block motor resolution. The primary outcome timepoint of 60-minutes post-motor resolution is indicated by a vertical bold dotted line in A. The QST values for the block and control arm are shown in red and blue, respectively. The baselines for the block and control arms are represented as horizontal dotted lines in red and blue, respectively. Average baseline and block onset times prior to motor resolution are also indicated with vertical dotted lines, as labeled in A.

Baseline skin temperatures were similar between arms. At the time of full motor block onset, the block arm temperature was significantly higher than the control arm (median [IQR]: block:33.8 [32.6, 34.3], control:26.8 [25.7, 28.3], p<0.001; Supplemental Figure 2). Block arm temperature was also higher than control arm at the time of full motor resolution (mean±SD: block:32.0±1.6, control:27.1±2.7; p<0.001) but was similar to control arm by 120 minutes after MR (T120, block:27.9±2.7, control:27.7±2.8, p=0.224).

Changes in Pain Sensitivity after Block Resolution

Change in Heat Pain Threshold (Primary Outcome)

Heat Pain threshold (1/10 pain) at the 60-minute post-MR timepoint (T60) was predefined as the primary outcome. There was no significant difference between the block and control arms (block:40.8±2.2°C, control:41.2±2.6°C; 95%CI[−0.99, 0.17]; p=0.160; Figure 2A). We did not observe sensitivity differences between arms in exploratory secondary analyses of other sensory modalities at T60 (Figure 2C-J), except for heat pain threshold (5/10 pain), where control arm was slightly less sensitive than block arm (block:43.1±2.7°C, control:43.7±2.9°C; 95%CI[−1.06, −0.01]; p=0.047, Figure 2B). This difference was not present after accounting for baseline thresholds (Supplementary Figure 3).

Exploring Point of Maximal Sensitization during the 3-hours after Block resolution

Considering that 60-min post-MR may occur before full sensory recovery for some participants, and given variability in block resolution, we examined nociceptive sensitivity across the entire 3-hour post-MR period. For each participant and QST modality, we identified the point of maximal sensitivity during the entire period of testing. We then compared this maximally sensitized value between the block and control arms (Table 2).

Table 2. Maximally sensitized values of each QST at any timepoint post-motor resolution for each participant.

Comparison of the maximal deviation between the block and control arms showed no evidence that the block arm became more sensitive than the control arm. In some cases, the control arm exhibited more sensitized values than the previously blocked arm. p < 0.05 was considered significant.

	Control arm	Block arm	Difference in arms (block - control)		p-value
	(mean ± std)	(mean ± std)	(mean ± std)	95% CI
Heat Pain Detection Threshold (°C)
1/10 pain	38.9±1.5	39.0±1.6	0.2±1.1	−0.2, 0.5	0.480b
5/10 pain	41.3±2.8	41.3±2.6	0.1±1.4	−0.4, 0.5	0.839a
10/10 pain	44.7±2.8	44.6±2.7	−0.1±1.1	−0.5, 0.3	0.588a
Punctate Pain Thresholds (monofilament size)
Punctate pain detection threshold	5.6±0.9	5.8±0.8	0.2±0.5	0.1, 0.4	0.005 b
Suprathreshold Punctate Pain Ratings (NRS: 0–10)
Punctate pain rating	3.7±2.2	3.3±2.5	−0.5±1.0	−0.8, −0.2	0.007 b
Temporal Summation of Pain and Painful After Sensations (NRS: 0–10)
Temporal summation of punctate pain	4.2±1.9	3.9±2.3	−0.3±1.4	−0.7, 0.2	0.260a
Painful after sensations	0.6±1.1	0.1±0.4	−0.6±1.0	−0.9, −0.3	0.001 b
Pressure Pain Threshold and Tolerance (lbs of force)
Forearm pressure pain threshold	6.0±2.1	6.1±2.2	0.0±1.6	−0.5, 0.6	0.886a
Forearm pressure pain tolerance	9.6±3.6	9.54±3.66	−0.1±2.1	−0.8, 0.6	0.755a
Trapezius pressure pain threshold	7.8±2.3	8.0±2.6	0.2±2.0	−0.5, 0.8	0.631a
Trapezius pressure pain tolerance	11.4±4.0	11.6±3.7	0.1±1.5	−0.4, 0.6	0.429b
Cuff Pressure Threshold (mmHg)
Pressure pain threshold	192.8±74.0	201.5±83.3	8.7±40.7	−5.3, 22.7	0.351b

Abbreviations: NRS = numerical pain rating scale; °C = degrees Celsius; lbs = pounds; mmHg = millimeters of mercury

^apaired T-test was used for parametric data

^bWilcoxon signed rank test was used for non-parametric data

Heat Pain Thresholds

There was no significant difference between the block and control arm when examining participants’ maximal sensitization value for heat pain thresholds over the 3-hour post-MR period. Specifically, the maximal sensitization for 1/10 heat pain threshold was similar between block and control arms (39.0±1.6°C vs. 38.9±1.5°C; p=0.480). A similar pattern was observed for the maximal sensitization for 5/10 heat pain threshold (block:41.3±2.6°C; control:41.3±2.8°C, p=0.839) and 10/10 heat pain threshold (block:44.6±2.7°C; control:44.7±2.8°C, p=0.588; Figure 3A-C).

Figure 3. Paired differences of the maximally sensitized values occurring in the 3-hours after block resolution across a range of QSTs.

Individually paired differences of the maximally sensitized values for the block (red) and control arms (blue). *represents significant paired differences between block and control arms (p< 0.05).

Punctate Pain Threshold

When examining participants’ maximal sensitization value using the von-Frey monofilament for punctate pain detection threshold, we observed greater sensitization in the control than the blocked arm (control:5.6±0.9; block:5.8±0.8 p=0.005; Figure 3D).

Suprathreshold Punctate Pain

Similarly, when examining participants’ maximal sensitization value using ratings of suprathreshold pinprick pain, we observed greater sensitization in the control arm compared to the block arm (control:3.7±2.2, block:3.3±2.5, p=0.007; Figure 3E).

Pressure Pain threshold and tolerance

No significant differences were observed between the block and control arms in the maximal sensitization value for forearm pressure pain threshold or tolerance, assessed using either the handheld algometer or circumferential cuff (Figure 3H-J). Similarly, no differences were observed in the maximal sensitization value for pressure pain threshold or tolerance in a non-blocked area (trapezius).

Temporal Summation of Pain and Painful After Sensations

Using a train of 10 applications of a weighted mechanical pinprick probe to the index finger, participants’ temporal summation of pain (10^th-1^st pain rating) was assessed, followed by rating of lingering pain in the area 15 seconds later (PAS). Maximal TSP value did not differ between the block and control arms (p>0.05; Figure 3F), but maximal PAS were higher in the control arm (control:0.6±1.1, block:0.1±0.4, p=0.001; Figure 3G).

Time-course of changes in sensitivity accounting for baseline differences

Due to small baseline differences between arms, we conducted an exploratory analysis to account for these differences, calculating change from baseline (post-block value-baseline). Comparing this change from baseline between arms revealed greater change towards the sensitized direction in control compared to blocked arm for several of the QSTs (Supplemental Figure 3).

Discussion

In this healthy volunteer study, we aimed to determine whether objective pain sensitization occurs in the hours after nerve block resolution. We applied calibrated painful stimuli across multiple modalities (heat and pressure-based painful stimuli) to both an arm that received an axillary brachial plexus block, and the contralateral unblocked arm, allowing for paired, within-participant comparisons. We found no evidence of sensitization in heat pain detection threshold (1/10 pain) compared between arms at 60-minutes post-MR. Recognizing that participants showed varied trajectories of motor and sensory block resolution, we also identified each participant’s maximally sensitized value for multiple pain modalities during and after nerve block resolution, including a 3-hour post-MR period. Again, we observed no evidence of sensitization in the blocked arm. In fact, the control arm often showed greater sensitization compared with its own baseline value, while this was essentially not observed in the block arm. One possible explanation is that repeated exposure to mildly painful tests for several hours in an arm without a block may have increased pain sensitivity, although this theory requires further study.

Rebound pain is described as a significant increase in pain to severe levels, that patients may experience after nerve block resolution, particularly following a single injection technique. This sudden increase in pain can be disconcerting for patients, may be associated with increased opioid consumption, and can potentially delay discharge or result in readmission.^18,19 Some descriptions of rebound pain have suggested that the nerve block itself may amplify the pain signal at a molecular level. For example, a previous study in a rodent model demonstrated transient hypersensitivity to a heat and mechanical pressure pain threshold testing at 3-hours after perineural sciatic injection with ropivacaine, but not at 5–7 hours or 12–14 days postoperatively.²⁰ Contrary to this idea, our study in this human volunteer model did not find evidence of block-induced hypersensitivity. These findings suggest that the phenomenon of rebound pain is more likely driven by the surgical pain that suddenly emerges once the block has resolved. This highlights the importance of a well-timed application of adjuvant multimodal analgesics before regional anesthesia wears off, to prevent rebound pain.^5,18,19,21 Importantly, extending the duration of the regional anesthetic to align with the expected duration of postoperative pain, using a continuous regional anesthetic technique, may obviate the problem of rebound pain.^5,22,23

In addition, pharmacologic strategies that have been used to extend block duration and thus reduce the impact of rebound pain, include the use adjuvants such as dexamethasone.^23–27 Behavioral strategies, especially patient education, may allow reasonable expectation-setting for variations in pain, as the nerve block resolves, and the need to use other analgesics in this period.¹⁸ Risk factors for rebound pain include younger age, females sex, higher anxiety or depression, pre-existing pain, and opioid tolerance.^2,5 Thus, approaches to decrease rebound pain (continuous regional catheters, local anesthetic adjuvants, multimodal analgesic management, preoperative teaching) are particularly relevant for patients with these characteristics. Future investigation of sensitivity in preoperative patients may also allow assessment of post-block hypersensitivity in those individuals who already have acute or chronic pain.

Limitations

The strengths of our study include the within-subject design, where each participant served as their own control, and the comprehensive and longitudinal testing. However, there are important limitations to our study which must be considered. Participants did not undergo surgery, so the cascade of events that occur following a surgical incision, including surgical pain, were not present.²⁸ Furthermore, blinding of participants and the QST tester was not possible, as the blocked arm displayed obvious motor loss, raising the potential for expectation bias. Nonetheless, when possible, the participant was shielded from any screen displaying the numerical values associated with their QSTs, such as the numeric pounds of pressure being applied or degrees of temperature of the thermode. The arm receiving the block was randomized to minimize dominance effects. Despite this, at baseline, the blocked arm was, on average across the group, slightly more sensitive compared to the control arm.

Supplemental Figure 3 shows that even when accounting for baseline in the ipsilateral arm, we did not observe increased sensitivity in the block arm compared to control. Interestingly, there may be evidence that the presence and gradual resolution of the nerve block may even be protective against sensitization that occurred with repeated pain testing, although this requires further investigation. We also acknowledge that our study was powered for a large effect size, and smaller effects within the sample may have been missed.

Our primary outcome timing (T60; 60-minutes post-MR) did not fully account for variability in block resolution, although all participants had sensory resolution prior to T60 except for one participant, who had sensory resolution at 70 minutes after MR. However, our measures to determine motor and sensory recovery lack the sensitivity to be able to detect differential nerve fiber blockade. Importantly, to ensure that we had not missed the most sensitive value if it occurred later, we extracted each participant’s maximally sensitized value over a longer time course, during which sensory block most certainly would have resolved (3-hour post-MR). Others have previously reported a slightly earlier, but variable, return of motor than sensory function after axillary brachial plexus block with 20ml of mepivacaine 1.5% (similar dose to our study), with MR at 254 minutes (226–282) and sensory (256 minutes (230–282).¹⁶ We therefore chose to anchor the start of nociceptive testing with return of motor function, increasing the likelihood of capturing the critical window when sensory resolution returned and hypersensitivity would theoretically occur. Therefore, to ensure that we had not missed the most sensitive value if it occurred later, we extracted each participant’s maximally sensitized value over the duration of nerve block resolution, including MR and 3-hour post-MR. However, these values also consistently showed no evidence of hypersensitivity in the blocked arm. Additionally, our study used a variety of modalities of pain testing, but focused around threshold testing of heat pain, punctate pain, and pressure pain, as we considered that this would allow the most sensitive testing. While we also employed some suprathreshold-based pain tests, it is possible that the use of other QSTs (i.e. cold pressor test) might reveal hypersensitivity where the tests we used did not.

Conclusion

In this study, no evidence for post block hypersensitivity was detected following a unilateral axillary brachial plexus block in healthy volunteers. In contrast, the mild sensitization occurring in the control arm compared to baseline, which was not observed in the blocked arm after resolution, may suggest a protective effect of nerve block against sensitization with repeated pain testing. However, this needs to be formally and intentionally assessed in future studies before such a conclusion could be drawn. Overall, our study suggests that clinically observed rebound pain is more likely caused by the simple return of surgical pain. Provision of adequate regional anesthetic duration, application of adjuvant analgesic modalities, and management of patient expectations may be a better strategy to managing rebound pain rather than simply avoiding regional anesthesia.

Supplementary Material

Supplemental Figure 2

Supplemental Figure 2. Temperature differences between arms.

Supplemental Figure 3

Supplemental Figure 3. Accounting for average baseline QST differences.

Supplemental Figure 1

Supplemental Figure 1. Participant time courses for 1/10 heat pain.

Abbreviations and acronyms:

ASA

American Society of Anesthesiologists

HPDT

Heat pain detection threshold

IQR

Interquartile Range [25, 75]

MR

Motor resolution

NRS

Numerical pain rating scale

PAS

Painful after sensations

PCS

Pain catastrophizing scale

Post-MR

Post-motor resolution

QST

Quantitative sensory testing

SINB

Single injection nerve block

TSP

Temporal summation of pain