Pharmacological Treatments of Neuropathic Pain

Real-Life Comparisons Using Propensity Score Matching

Xavier Moisset; M. Gabrielle Pagé; Bruno Pereira; Manon Choinière

Pain. 2022;163(5):964-974.

Abstract and Introduction

Abstract

Studies comparing different drug treatments for chronic neuropathic pain (NP) are very limited. We, therefore, examined 4 recommended treatments, namely, antidepressants (duloxetine, venlafaxine, and tricyclic antidepressants), antiepileptics (gabapentine and pregabalin), weak opioids, and strong opioids, among patients with NP evaluated before first visit in a tertiary pain treatment centre and 6 months later. Patients with both a clinical diagnosis of NP and a DN4 score ≥3/7 were selected from patients enrolled in the Quebec Pain Registry. Each participant was assigned an inverse weighting of the probability of receiving any NP treatment, taking into account their age, sex, baseline pain intensity, pain duration, pain catastrophizing tendency, education level, employment, and comedications at 6-month follow-up (M6). Patients were considered as improved if they presented at least a 30% reduction on average pain intensity at M6 compared with baseline. A total of 944 patients completed both baseline and M6 evaluations. Overall, 23.0% of patients were significantly improved for pain intensity at M6. There was no significant difference in proportions patients taking or not antidepressants, gabapentinoids, or weak opioids. Among patients taking strong opioids (N = 288), 13.9% (N = 40/288) were improved vs 27.0% (177/656) of those who were not on opioids (P < 0.004). Inverse probability of treatment weighting confirmed that the proportion of patients who improved was significantly lower among those taking strong opioids compared with those who did not (P < 0.001). In conclusion, long-term use of strong opioids is a treatment suited for a limited proportion of patients with chronic NP.

Introduction

Neuropathic pain (NP) is present in 7% to 10% of the general population.^[30] It is often difficult to treat, and it has a major impact on patients' quality of life along with important direct and indirect healthcare costs.^[1,13,16] Several epidemiological studies have shown that many patients with NP do not receive recommended treatments.^[1,17,45] Nonetheless, pharmacological and nonpharmacological therapies, although imperfect, are available.^[15,23,37] Current international guidelines for pharmacological management of NP recommend tricyclic antidepressants, serotonin–noradrenaline reuptake inhibitors (SNRIs), and gabapentinoids (pregabalin and gabapentin) as first-line treatment; tramadol as second-line treatment; and strong opioids as third-line treatment.^[23] To date, the number of studies comparing different recommended drug regimens for NP is very limited,^{[3,22,23,26,31,37,48]} although comparative efficacy of different drugs could be informed, to some degree, by meta-analyses of placebo-controlled drug trials that allow for the estimation of number needed to treat for each agent allowing, with some recognized limitations, for a quantitative comparison across different drugs.^[23,40] However, knowing the comparative clinical effectiveness of these treatments in real-world settings would be of major importance.

The Quebec Pain Registry (QPR) has been implemented in 2008 in 3 university-affiliated multidisciplinary pain treatment centres in Quebec (Canada) and 2 other centres joined in 2012. Close to 9,000 patients have been included and have provided consent for their data to be used for research purposes. Among these patients, around 20% were presenting chronic NP. As pain was systematically and comprehensively assessed both at baseline (before first appointment at the pain clinic) and 6 months later, it is possible to use such data to compare treatment effectiveness in this selected population of patients. Indication bias is frequent in observational studies because the choice of treatment is generally influenced by the patients' characteristics (eg, age, sex, and presence of depression or sleep problems)^[2] and contraindications (eg, cardiac conduction block or postural hypotension for tricyclic antidepressants and substance use disorder for opioids), cost or healthcare provider coverage, and patient preference. However, a propensity score (PS) can be determined to adjust for several of these differences.^[2]

The aim of this study was to examine the clinical evolution of patients with chronic NP treated in tertiary care centres and compare in real-life clinical settings the effectiveness of recommended medication for NP using a PS analysis.

1 2 3 4 5

Next Section

Table 1. Baseline characteristics of the 944 patients with chronic neuropathic pain.
Variables	Values
Age, y (mean ± SD)	53.4 ± 13.3
Female sex, % (n)	51.4 (485)
Pain duration, y (median [IQR])	3.0 [1.0–8.0]
Anglo-American ethnicity, % (n)	93.0 (878)
Presence of allodynia, % (n)	22.1 (209)
Presence of hypoesthesia, % (n)
To touch	39.8 (376)
To prick	39.6 (374)
At least one hypoesthesia	43.8 (413)
Average pain intensity in the past 7 days (mean ± SD)	6.8 ± 1.9
Brief Pain Inventory pain interference score in the past 7 days (mean ± SD)	5.9 ± 2.1
Beck depression Inventory-I, % (n)
0–9: normal range	19.9 (188)
10–18: mild to moderate depression	35.5 (335)
19–29: moderate–severe depression	30.4 (287)
30–63: severe depression	14.1 (133)
Sleep Problem Index (score 0–30) (mean ± SD)	18.3 ± 8.4
Pain Catastrophizing Scale (score 0–52) (mean ± SD)	29.8 ± 12.7
Quality of life
SF-12 Norm-Based Physical Summary Scale (mean ± SD)	28.2 ± 8.0
SF-12 Norm-Based Mental Health Summary Scale (mean ± SD)	41.0 ± 11.6
Nonpharmacological treatments, % (n)
Psychological	63.1 (596)
Physical	64.0 (604)
Education level, % (n)
Primary	8.5 (59)
Secondary	40.4 (281)
CEGEP or technical school	32.1 (223)
University	18.1 (126)
Work type, % (n)
Full-time job	19.7 (137)
Part-time job	7.3 (51)
No job	73.0 (508)

Psychological treatments correspond to relaxation, meditation, hypnosis, visualisation, distraction, psychotherapy, group therapy, self-help support group, and others. Physical treatments correspond to physiotherapy, occupational therapy, hydrotherapy, transcutaneous nerve stimulation, intramuscular stimulation, ultrasound, biofeedback, acupuncture, massage, chiropractic, ostheopathy, therapeutic touch, reflexology, Reiki, magnet therapy, exercises at home, and others.
CEGEP, French acronym for "general and professional teaching college"; IQR, interquartile range; SF-12, 12-item Short Form Survey.

Table 2. Pharmacological pain treatments used before to the first visit at the pain clinic with reason for discontinuation (possibility to note more than one reason for discontinuation) and treatment used at baseline for the 944 patients with complete evaluation both at baseline and 6-month follow-up.
	Previously used pain treatments (N = 944)	Pain treatments used at baseline (N = 944)
Antidepressants	118 (12.5)	148 (15.7)
Stopped (%) because of
Side effects	56.3
Lack of benefit	36.1
Antiepileptics	245 (26.0)	342 (36.2)
Stopped (%) because of
Side effects	58.6
Lack of benefit	39.1
At least one first-line antineuropathic drug, n (%)	294 (31.1)	400 (42.4)
Acetaminophen, n (%)	171 (18.1)	367 (38.9)
Stopped (%) because of
Side effects	32.7
Lack of benefit	53.4
NSAIDS	245 (26.0)	271 (28.7)
Stopped (%) because of
Side effects	31.9
Lack of benefit	48.0
Weak opioids	147 (15.6)	94 (10.0)
Stopped (%) because of
Side effects	44.9
Lack of benefit	43.6
Strong opioids	285 (30.2)	292 (30.9)
Stopped (%) because of
Side effects	43.3
Lack of benefit	26.4
Cannabinoids	25 (2.7)	50 (5.3)
Stopped (%) because of
Side effects	50.0
Lack of benefit	15.4
Antispastic drugs	87 (9.2)	78 (8.3)
Stopped (%) because of
Side effects	34.1
Lack of benefit	45.5
Ketamine	6 (0.6)	5 (0.5)
Topical capsaicin	2 (0.2)	2 (0.2)
Topical lidocaine	1 (0.1)	3 (0.3)

NSAIDs, nonsteroidal anti-inflammatory drugs.

Table 3. Pharmacological pain treatments used during the 6 months after the first visit (M0) at the pain clinic, either discontinued (with reason for discontinuation, possibility to note more than one reason) or used 6 months after the first visit (M6).
	Pain treatments discontinued within 6 months after initial appointment at the pain clinic (N = 944)	Pain treatments used at 6 months (N = 944)	Pain treatments initiated after initial appointment at the pain clinic (N = 944)	Ongoing pain treatments before initial appointment that was continued until at least the 6-month follow-up (N = 944)
Antineuropathic antidepressants	107 (11.3)	189 (20.0)	88 (9.3)	101 (10.7)
Stopped (%) because of
Side effects	48.7
Lack of benefit	22.6
No more needed	18.3
Antineuropathic antiepileptics	158 (16.7)	364 (38.6)	136 (14.4)	228 (24.2)
Stopped (%) because of
Side effects	46.1
Lack of benefit	19.4
No more needed	20.6
At least one first-line antineuropathic drug, n (%)	236 (25.0)	433 (45.9)	197 (20.9)	236 (25.0)
Acetaminophen, n (%)	146 (15.5)	343 (36.3)	98 (10.4)	245 (25.9)
Stopped (%) because of
Side effects	19.0
Lack of benefit	21.5
No more needed	33.9
NSAIDS	147 (15.6)	224 (23.7)	136 (14.4)	88 (9.3)
Stopped (%) because of
Side effects	15.0
Lack of benefit	22.8
No more needed	37.1
Weak opioids	115 (12.2)	94 (10.0)	46 (4.9)	48 (5.1)
Stopped (%) because of
Side effects	35.9
Lack of benefit	20.3
No more needed	23.4
Strong opioids	190 (20.1)	288 (30.5)	90 (9.5)	198 (21.0)
Stopped (%) because of
Side effects	24.6
Lack of benefit	16.4
No more needed	35.9

The third and fourth columns correspond to subgroups of patients included in the second column. Indeed, among ongoing treatments at Month 6, some were present at baseline (column 4), whereas others were initiated during the initial appointment or during the following 6 months (column 3).
NSAIDs, nonsteroidal anti-inflammatory drugs.

Table 4. Evolution of pain intensity, pain interference, sleep, catastrophizing, health-related quality of life, and depression from baseline to 6-month follow-up (M6).
	Baseline (N = 944), mean ± SD	M6 (N = 944), mean ± SD	Effect size [95% CI], Cohen d	P
Average pain intensity in the past 7 days	6.8 ± 1.9	5.9 ± 2.3	0.37 [0.31–0.43]	<0.001
	Relative average pain intensity variation between M0 and M6, % (n)
≥50% pain decrease		13.6 (128)
≥30% pain decrease		23.0 (217)
≥10% pain decrease		50.9 (480)
Stable pain (variation < 10%)		23.9 (226)
≥10% pain increase		25.2 (238)
≥30% pain increase		9.5 (90)
≥50% pain increase		5.0 (47)
Brief Pain Inventory interference score in the past 7 days (global score)	5.9 ± 2.1	5.0 ± 2.5	0.42 [0.36–0.49]	<0.001
	Relative pain interference variation between M0 and M6, % (n)
≥50% pain decrease		16.2 (153)
≥30% pain decrease		30.6 (289)
≥10% pain decrease		51.3 (484)
Stable pain (variation <10%)		27.3 (258)
≥10% pain increase		21.4 (202)
≥30% pain increase		10.7 (101)
≥50% pain increase		6.6 (62)
Sleep problem index (score 0–30)	18.3 ± 8.4	15.5 ± 9.2	0.37 [0.30–0.43]	<0.001
Quality of life
SF-12 Physical Summary Scale	28.2 ± 8.0	30.3 ± 9.1	0.28 [0.22–0.35]	<0.001
SF-12 Mental Health Summary Scale	41.0 ± 11.6	41.9 ± 11.8	0.08 [0.02–0.15]	0.010
	% (n)	% (n)	Cramér's V
Beck Depression Inventory, % (n)			0.09 [0.05–0.12]	<0.001
0–9: normal range	19.9 (188)	25.6 (241)
10–18: mild-to-moderate depression	35.5 (335)	34.5 (325)
19–29: moderate-to-severe depression	30.4 (287)	26.5 (249)
30–63: severe depression	14.1 (133)	13.4 (126)

CI, confidence interval; SF-12, 12-item Short Form Survey.

Table 5. Mean pain intensity variation from baseline to 6-month follow-up depending on the type of medications taken at baseline.
Treatment (number of patients taking the medication, of 944)	Taken at baseline, median [IQR]	Not taken at baseline, median [IQR]	Difference, median [IQR]	P
Weak opioids (n = 94 vs 850)	−1 [−3 to 0]	−1 [−2 to 1]	0 [−0.54 to 0.51]	0.111
Strong opioids (n = 292 vs 652)	0 [−2 to 1]	−1 [−2 to 0]	1 [0.65 to 1.35]	0.451
Antiepileptics (n = 342 vs 602)	−1 [−2 to 1]	0 [−2 to 1]	−1 [−1.33 to 0.66]	0.396
Antidepressants (n = 148 vs 796)	0 [−2 to 1]	−1 [−2 to 0]	1 [−0.56 to 1.44]	0.270

A negative value for pain variation is in favor of a pain decrease between baseline and M6.
IQR, interquartile range.

Table 6. Mean pain intensity variation from baseline to 6-month follow-up (M6) depending on the type of medications taken at M6.
Treatment (number of patients taking the medication, of 944)	Taken at M6, median [IQR]	Not taken at M6, median [IQR]	Difference, median [IQR]	P
Weak opioids (n = 94 vs 850)	0 [−2 to 0]	−1 [−2 to 1]	1 [−0.46 to 1.53]	0.853
Strong opioids (n = 288 vs 656)	0 [−1 to 1]	−1 [−2 to 0]	1 [0.65 to 1.35]	0.012
Antiepileptics (n = 364 vs 580)	−1 [−2 to 0]	0 [−2 to 1]	−1 [−1.33 to 0.67]	0.351
Antidepressants (n = 189 vs 755)	0 [−2 to 0]	−1 [−2 to 1]	1 [−0.60 to 1.40]	0.716

A negative value for pain variation is in favour of a pain decrease between baseline and M6. IQR, interquartile range.

Table 7. Characteristics of patients receiving strong opioids at 6-month follow-up or not, before application of the propensity score and after application of the inverse probability of the treatment weighting method.
	Before propensity score			After inverse probability of treatment weighting
	Opioids (n = 288)	No opioids (n = 656)	P	Opioids (n = 288)	No opioids (n = 656)	·d·	P
Age, y (mean ± SD)	52.7 ± 12.5	53.7 ± 13.6	0.28	53.2 ± 12.8	53.2 ± 13.7	0.002	0.99
Female sex	137 (47.6%)	348 (53.1%)	0.12	51.3%	51.2%	0.002	0.98
Pain duration, y (median [IQR])	4.0 [1.5–9.5]	3.0 [1.0–7.0]	<0.001	3.0 [1.3–8.0]	3.0 [1.3–8.0]	0.021	0.79
Average pain intensity in the past 7 days at baseline (mean ± SD)	7.1 ± 1.8	6.6 ± 2.0	<0.001	6.8 ± 1.8	6.8 ± 1.9	0.021	0.79
Percentage (%) of patients with at least 30% pain intensity decrease	13.9	27.0	<0.001	14.2	26.0	0.298	<0.001
Brief Pain Inventory pain interference score in the past 7 days (mean ± SD)	6.4 ± 2.0	5.7 ± 2.1	<0.001	6.0 ± 2.1	5.9 ± 2.1	0.051	0.58
Percentage (%) of patients with at least 30% pain interference decrease	23.3	33.9	<0.001	22.5	32.6	0.228	0.003
Antiepileptics (yes, n (%))	159 (55.2%)	205 (31.3%)	<0.001	36.1	38.8	0.056	0.48
Antidepressants (yes, n (%))	94 (32.6%)	95 (14.5%)	<0.001	20.4	19.5	0.021	0.78
Weak opioids (yes, n (%))	16 (5.6%)	78 (11.9%)	0.003	13.5	10.0	0.108	0.34
Nonpharmacological treatments (%)
Psychological							0.04
Never used	28.5	40.6	<0.001	34.3	38.3	Ref
Past use	67.7	54.0		62.8	54.8	0.120
Current use	3.8	5.5		2.9	6.9	0.230
Physical							0.82
Never used	34.7	36.7	0.78	34.8	36.4	Ref
Past use	56.9	56.1		58.5	56.2	0.042
Current use	8.3	7.3		6.6	7.4	0.024
PCS (mean ± SD)	31.9 ± 12.8	28.9 ± 12.6	<0.001	29.8 ± 12.5	29.0 ± 13.4	0.063	0.51
Education (%)			0.004				0.92
Primary	9.8	7.4		7.6	8.2	Ref
Secondary	42.5	34.5		35.3	37.4	0.008
CEGEP or technical school	29.6	28.8		30.8	28.7	0.060
University	18.1	28.8		26.2	25.7	0.041
Work (yes, n (%))			<0.001				0.75
Full-time job	13.5	23.5		21.4	20.4	Ref
Part-time job	4.5	8.7		6.3	8.2	0.078
Others	81.9	67.8		72.3	71.4	0.014
SF-12 Mental (mean ± SD)	39.3 ± 11.3	41.8 ± 11.6	0.003	41.8 ± 11.5	41.1 ± 11.6	0.061	0.47

Antineuropathic antiepileptics, antidepressants, and weak opioids correspond to treatments received at M6.
CEGEP, French acronym for "general and professional teaching college"; ·d·, standardized difference (difference is not significant when ·d·< 0.20); IQR, interquartile range; PCS, Pain Catastrophizing Scale; PCS, Pain Catastrophizing Scale; SF-12, 12-item Short Form Survey.