Smallest clinically meaningful improvement in amputation-related pain and Brief Pain Inventory scores as defined by patient reports of global improvement after cryoneurolysis: A retrospective analysis of a randomized, controlled clinical trial

Abstract

Background.

The smallest meaningful improvement in pain scores (“minimal clinically important difference”, MCID) following an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis.

Methods.

In the original trial we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis who had no subsequent participant interaction. At both baseline and 4 months (primary endpoint) participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory’s interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change. The smallest clinically meaningful improvement in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the Patient Global Impression of Change.

Results.

The median [IQR] phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1, 1], 3 [3, 4], and 4 [3, 6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 8 [6, 18], 24 [22, 31], and 34 [22, 46]. The proportions of patients that experienced PGIC ≥ 5 were 33% and 36% in Active and Placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥ 5 in the Active group compared to Sham group with 95% confidence interval was 0.9 (0.6, 1.4), P = 0.667.

Conclusions.

Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was slightly larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design.

Clinicaltrials.gov:

NCT03449667 (Principal Investigator: Brian M. Ilfeld, MD, MS; initial posting: February 28, 2018)

Introduction

The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommends the use of the numeric rating scale (NRS) to assess pain within clinical investigations,¹ and is applied nearly universally. Similarly, the IMMPACT also advocates the evaluation of impairment in physical and emotional functioning with an instrument such as the Brief Pain Inventory.¹ Considering both are recorded using an ordinal scale, statistical significance is frequently identified. However, what constitutes a clinically meaningful improvement to patients remains imperfectly defined.² Establishing the smallest clinically meaningful improvement—also termed “minimal clinically relevant difference” (MCID)—enables adequate prospective study design and power, as well as the evaluation of previously published trial data.

The smallest clinically meaningful improvement may be calculated using an anchor-based method by correlating NRS and Brief Pain Inventory scores to patients’ own assessment of their improvement, such as the Patient Global Impression of Change scale (PGIC), as recommended by the IMMPACT.¹

We therefore used an anchor-based method to reanalyze a recently published multicenter clinical trial involving the use of percutaneous cryoneurolysis to treat chronic post-amputation phantom limb pain.³ A prolonged neural block is provided with cryoneurolysis which entails the application of very low temperatures (approximately −70°C using nitrous oxide) to reversibly ablate peripheral nerves.⁴ A total of 144 participants were enrolled in the original clinical trial and randomized to either active treatment or a sham procedure.³ The difference between treatment groups was not statistically significant for the primary outcome measure—the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10); but the dataset nevertheless provides a valuable opportunity to help define the smallest clinically meaningful improvement in NRS and the Brief Pain Inventory.

Methods

The original trial followed Good Clinical Practice and was conducted within the ethical guidelines outlined in the Declaration of Helsinki. The trial was registered prior to patient enrollment (NCT03449667; Principal Investigator: Brian M. Ilfeld, M.D., M.S.; initial posting: February 28, 2018). The Institutional Review Board approved the protocol at each of the 6 enrolling centers as well as the United States Army Medical Research and Development Command Human Research Protection Office. An independent Data Safety Monitoring Board was responsible for the conduct and oversight of all aspects of the investigation. Written, informed consent was obtained from all participants. Deidentified data were used for the current secondary analysis.

Original trial.

Protocol details and results of the original trial have been published previously.³ In short, patients with a lower-limb amputation and established phantom pain received a single-injection ropivacaine femoral and sciatic peripheral nerve block. They were subsequently randomized to receive either an ultrasound-guided percutaneous cryoneurolysis treatment or a sham procedure in a participant- and observer-masked fashion. The original primary outcome was the average intensity of phantom limb pain 4 months following the intervention as measured on a 0-10 numeric rating scale within the Brief Pain Inventory, short form. An optional crossover treatment 4-6 months following the initial intervention allowed all participants the opportunity to ensure they received an active treatment, but because it was optional also introduced selection bias from this time point forward. Consequently, we now include only data collected at the 4-month primary outcome timepoint prior to the optional crossover intervention.

Current analysis.

To provide a global measure of worsening or improvement, the Patient Global Impression of Change (PGIC) was administered allowing patient evaluation of integrated treatment effects.⁵ This measure is a 7-point ordinal scale requiring the patient to rate the current intensity of phantom limb pain compared to their pre-treatment baseline: 1 for “very much worse” to 7 for “very much improved” (4 is “no change”). We used this scale to determine what the participants of our study considered small, medium and large NRS improvements. Specifically, we report the change in average NRS pain score for each of 5 categories: worsening (PGIC 1-3), no improvement (PGIC = 4), small improvement (PGIC = 5), medium improvement (PGIC = 6), and large improvement (PGIC = 7). We used a Chi squared test to examine the relationship between Treatment (Sham vs Active) and any improvement defined by PGIC ≥ 5.

The primary instrument of the original investigation was the Brief Pain Inventory, short form, which assesses pain and its interference with physical and emotional functioning.⁶ The form includes three domains: (1) pain, with four questions using an NRS to evaluate 4 pain levels: “current”, “least”, “worst”, and “average”; (2) percentage of relief provided by pain treatments with one question; and, (3) interference with physical and emotional functioning using a 0-10 scale (0 = no interference; 10 = complete interference). The seven interference questions involve general activity, mood, walking ability, normal work activities (both inside and outside of the home), relationships, sleep, and enjoyment of life.⁶ The seven functioning questions can be combined to produce an interference subscale (0-70). The use of both single items (e.g., mood) and the composite scores is supported by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for assessing pain in clinical trials.^5,7

The IMMPACT consensus statement specifies that “available data suggest that a change of 1 point on the Interference Scale [presumably for a single question]… would be a reasonable benchmark for future studies designed to identify minimally clinically important changes.”² However, it also notes that “because few studies have examined the importance of worsening on these measures, benchmarks are only provided for improvement in scores [emphasis added].”² To define amputee-specific clinically meaningful improvements in the Brief Pain Inventory, we used the PGIC data to determine the change in total Brief Pain Inventory interference subscale (7 questions added together) that patients considered to be a worsening (PGIC = 1-3), no improvement (PGIC = 4), and small (PGIC = 5), medium (PGIC = 6) or large (PGIC=7) improvement.

Results

A total of 144 participants were enrolled in the original clinical trial and randomized to either active treatment (n=71) or a sham procedure (n=73, Figure 1).³ The difference between treatment groups was not statistically significant for the primary and secondary outcome measures in the original trial. Eight participants did not have a PGIC recorded at Month 4, and thus 136 participants were included in the current analysis.

Figure 1.

CONSORT diagram.

The median [IQR] phantom limb pain NRS improvements considered small, medium, and large by patients were 1 [1, 1], 3 [3, 4], and 4 [3, 6], respectively (Table 1, Figure 2). Based on the PGIC at 4 months, the median [IQR] Brief Pain Inventory (interference subscale) improvement considered small, medium, and large by patients was 16 [6, 18], 24 [22, 31], and 34 [22, 46], respectively (Table 2). The proportions of patients that experienced PGIC ≥ 5 were 33% and 36% in Active and Placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥ 5 in the Active group compared to Sham group with 95% confidence interval was 0.9 (0.6, 1.4), P = 0.667.

Table 1.

Improvement in average phantom pain at 4 months defined as small, medium, and large by participants based on the Patients’ Global Impression of Change (PGIC). Eight patients did not have a PGIC response and were excluded (n=136).

Phantom Limb Pain Score Improvement (Numeric Rating Scale)
PGIC Descriptor	Worsening	None	Small	Medium	Large
PGIC Score	1 – 3	4	5	6	7
	(n=4)	(n=66)	(n=8)	(n=3)	(n=45)
Mean (SD)	−0.4 (0.5)	0 (1.0)	1.0 (0.9)	3.1 (0.7)	4.5 (1.9)
Mean (95%CI)	−0.4 (−1.1, 0.4)	0 (−0.2, 2.0)	1.0 (0.2, 1.8)	3.1 (2.2, 4.0)	4.5 (3.9, 5.2)
Median [IQR]	−0.3 [−0.6, 0]	0 [−0.5, 0.5]	1.0 [0.5, 1.3]	3 [3.0, 3.5]	4 [3.3, 5.5]

IQR: interquartile range [25^th, 75^th percentiles]

Figure 2.

Improvement in average phantom pain as measured on a numeric rating scale (NRS) defined by Patients’ Global Impression of Change (PGIC) 4 months following the intervention. Data expressed as median (dark horizontal bars) with interquartile range (IQR, Q1 to Q3) (box), minimum between maximum value and Q3+1.5*IQR and maximum between minimum value and Q1-1.5*IQR (whiskers). Scatter points represent the data points color-coded by the level of improvement: worsening (red), no change (blue), improvement (orange), and clinically meaningful improvement (green).

Table 2.

Improvement in the Brief Pain Inventory interference subscale at 4 months defined as small, medium, and large by participants based on the Patients’ Global Impression of Change (PGIC). Eight patients did not have a PGIC response and were excluded (n=136).

Brief Pain Inventory Improvement (Interference Subscale)
PGIC Descriptor	Worsening	None	Small	Medium	Large
PGIC Score	1 – 3	4	5	6	7
	(n=4)	(n=66)	(n=8)	(n=3)	(n=45)
Mean (SD)	−9 (9)	1 (7)	11 (11)	23 (12)	33 (17)
Mean (95%CI)	−9 (−22, −4)	1 (−1, 3)	11 (1, 22)	23 (8, 38)	33 (27, 39)
Median [IQR]	−8 [−2, −4]	0 (−2, 1)	16 (6, 18)	24 (22, 31)	34 (22, 46)

IQR: interquartile range [25^th, 75^th percentiles]

Discussion

This reanalysis of data from a previously published clinical trial identified that pain score decreases as little as 1 on the 0-10 NRS are deemed an improvement, albeit “small”, requiring a fall of 3-4 points to be described as a “medium” or “large” improvement. These values for patients undergoing ultrasound-guided percutaneous cryoneurolysis are similar to IMMPACT “benchmarks” of 1, 2, and 4 points representing “minimally important but perhaps not very important”, “much better”, and “substantial” changes in pain, respectively.² However, these values were based on three analyses,^8–10 and the smallest clinically important improvement can be significantly influenced by numerous patient characteristics such as geographic locality,¹¹ culture,¹¹ ethnicity,¹² age,¹³ sex,⁸ body mass index,¹³ educational level,¹⁴ perceived general health,¹⁴ disease and socioeconomic status,¹⁵ psychological (depression, anxiety, catastrophizing, etc.),^16,17 as well as pain baseline,⁸ duration, intensity, frequency, location, and etiology.² Therefore, there are countless differing patient populations, requiring “confirmation in other patient populations and different chronic pain syndromes”.¹⁰

Similarly, intervention tolerability, adverse effects, and safety all influence the evaluation of smallest clinically important improvements.^2,18 For example, a small analgesic benefit from a single minimally-invasive procedure with few significant risks such as ultrasound-guided percutaneous cryoneurolysis may be deemed more acceptable than a similar benefit from a daily medication with systemic side effects such as pregabalin or opioids.^8,19 To our knowledge, this is the first effort to define the MCID following a device intervention (ultrasound-guided percutaneous cryoneurolysis). And as noted by the IMMPACT, the duration of analgesic improvement should also be considered given that a small—yet long-lasting—analgesic benefit may be considered more acceptable than a similarly small benefit with a relatively short duration.² Perhaps as evidence of this concept, it is notable that the amputees of the current study considered the smallest important improvement to be a median [IQR] of 1.0 [0.5, 1.3] on the NRS when measured 4 months after the cryoneurolysis treatment,³ while a nearly-identical patient population deemed the smallest MCID to be twice as great (2.0 [0, 2.0]) when evaluated only 4 weeks following an ambulatory continuous peripheral nerve block.²⁰

Brief Pain Inventory.

Compared with the NRS, there is far less published data reporting on the smallest improvement within the Brief Pain Inventory deemed important to patients. The current analysis identified the improvements in the Brief Pain Inventory’s interference subscale (range 0-70) associated with small, medium, and large changes in pain scores as (median) 16, 24, and 34, respectively. These values greatly surpass the “benchmark” smallest clinically meaningful improvement of 1-2 points for each scale (7-14 for the total of 7 items) originally cited in the IMMPACT recommendations.² Our findings are supported by 144 additional amputees of the previously-mentioned study involving continuous peripheral nerve blocks which reported nearly identical values as the current analysis.²⁰

Limitations.

There are certain limitations to consider in this analysis. Firstly, we present secondary outcomes that were not part of the original protocol and statistical plan, making this a retrospective analysis of prospectively collected data. Additionally, our results are applicable only to patients with post-amputation phantom limb pain and may not be generalized to other common pain conditions. However, the specificity of our results to this particular population is also a strength of the study. Another limitation is that the Patient Global Impression of Change (PGIC) question did not differentiate between phantom and residual limb pain, but rather encompassed pain in general. This is evident in Figure 2, where 3 participants reported their pain as unchanged on the PGIC, despite the actual phantom limb pain score improving by 3 or more points between baseline and 4 months. Most participants experienced changes in both phantom and residual limb pain in the same direction (either improving or not), but a few cases demonstrated improvement in phantom pain alongside worsening in residual limb pain, leading the participant to respond that their overall “pain” had “worsened” (or vice versa). Lastly, there were few participants in the “small” and “medium” range of the PGIC relative to the number of participants rating their pain as unchanged or a “large” improvement, limiting our ability to identify the minimum clinically important difference for these subgroups.

In summary, patients with postamputation pain rate analgesic improvements as clinically meaningful similar to other chronic pain conditions and pharmacologic interventions, although their smallest meaningful improvement within the Brief Pain Inventory was significantly larger than the “benchmark” smallest clinically meaningful improvement originally cited in the IMMPACT recommendations. Determining clinically meaningful analgesic changes requires the study of populations with various pain conditions and different analgesic interventions. The results from this analysis will facilitate interpretation of data from published studies of similar populations and interventions, and guide future trial design by enabling investigators to adequately power future investigations.

Key Points.

Question.

Following a non-pharmacologic analgesic intervention, what is the smallest meaningful improvement in pain scores (“minimal clinically important difference”, MCID) and the Brief Pain Inventory measuring pain’s interference in physical and emotional functioning?

Findings.

For amputees with phantom limb pain treated with ultrasound-guided percutaneous cryoneurolysis, median [IQR] phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1, 1], 3 [3, 4], and 4 [3, 6], respectively; and the median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 8 [6, 18], 24 [22, 31], and 34 [22, 46].

Meaning.

Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was slightly larger than previously published values.

Glossary of Terms

IMMPACT

The initiative on Methods, Measurement, and Pain Assessment in Clinical Trials

NRS

numeric rating scale

MCID

minimal clinically relevant difference

PGIC

Patient Global Impression of Change scale