Pregabalin for the treatment of postoperative pain: results from three controlled trials using different surgical models

Figures & data

Figure 1 Design of the three clinical trials.

Abbreviations: bid, twice daily; IHR, inguinal hernia repair; TKA, total knee arthroplasty.

Table 1 Details of permitted preoperative, intraoperative, and postoperative anesthesia and analgesia techniques

	Preoperative	Intraoperative	Postoperative
Post-IHR	Premedication immediately prior to surgery included midazolam or temazepam, as needed. Patients could receive propofol for induction and sevoflurane, isoflurane, or desflurane.	Intraoperative analgesia was managed with fentanyl or sufentanil, as needed. Muscle relaxants were allowed during the surgical procedure.	Local infiltration of the surgical site at the end of surgery was specified as 20–30 mL (beneath external oblique fascia) of 0.5% bupivacaine. Standard analgesic medication consisted of 500 mg naproxen (bid) for 3 days and then as needed. If inadequate, a combination of 50 mg tramadol and 500–650 mg acetaminophen was administered every 4 hours, as needed. If still inadequate, 5 mg oxycodone and 500–650 mg acetaminophen was administered every 4 hours, as needed.
Post-TKA	Sedation with midazolam (0.05 mg/kg titrated to effect) or propofol (25–75 μg/kg/h) infusion. Use of PCA/PCEA to maintain pain at rest at ≤4 on the 11-point NRS.	Sedation with midazolam (0.05 mg/kg titrated to effect) or propofol (25–75 μg/kg/h) infusion. Anesthesia during the TKA was provided by epidural, spinal, or combined spinal/epidural analgesia with local anesthetic and hydromorphone or fentanyl.	Use of peripheral nerve block was allowed for the first 36 hours postsurgery. Patients then switched to oral analgesia 5 mg hydrocodone bitartrate/500 mg acetaminophen tablets every 4–6 hours as needed; or oxycodone/acetaminophen (up to the maximum dose) and/or intravenous opioid PCA (morphine, hydromorphone, fentanyl) depending on the site’s standard care. PCA/PCEA was used to maintain pain at rest at ≤4 on the 11-point NRS. After discontinuation of the epidural, oral warfarin, or low molecular weight heparin was used to avoid deep venous thrombosis prophylaxis.
Posthysterectomy	General anesthesia	Supplemental analgesia medication consisted of parenteral morphine (or similar opioid agent) by PCA pump, which was available immediately after surgery. For analgesia during the period before PCA was started, opioid analgesic was given by bolus injections.	Parenteral morphine (or similar opioid analgesic agent) was administered by PCA, as soon as possible postsurgery. Opioid analgesics were also administered by bolus injection, if required. If insufficient, additional opioid analgesia was administered by bolus injection. If opioid analgesia was inadequate or not well tolerated during the period when PCA was used, NSAID (naproxen, ibuprofen, diclofenac, ketorolac, or ketoprofen) and/or acetaminophen was added or substituted as appropriate.

Abbreviations: bid, twice daily; IHR, inguinal hernia repair; NRS, numerical rated scale; NSAID, nonsteroidal anti-inflammatory drug; PCA, patient-controlled analgesia; PCEA, patient-controlled epidural analgesia; TKA, total knee arthroplasty.

Figure 2 Participant disposition.

Abbreviations: AE, adverse event; GCP, good clinical practice; IHR, inguinal hernia repair; MITT, modified intent-to-treat population; PGB, pregabalin; TKA, total knee arthroplasty.

Table 2 Participant demographics

	Post-IHR				Post-TKA			Posthysterectomy
	Pregabalin			Placebo	Pregabalin		Placebo	Pregabalin		Placebo
	50 mg/d	150 mg/d	300 mg/d		150 mg/d	300 mg/d		150 mg/d	300 mg/d
	n=108	n=106	n=103	n=108	n=98	n=96	n=98	n=161	n=166	n=167
Mean age, years (SD)	48.4 (13.7)	48.8 (13.6)	48.4 (13.8)	47.2 (14.5)	63.0 (8.5)	63.7 (8.3)	63.3 (9.5)	44.9 (6.2)	44.6 (6.0)	44.4 (6.7)
Sex, n= female (%)	0	0	0	0	60 (61.2)	61 (63.5)	54 (55.1)	161 (100)	166 (100)	167 (100)
Race, n (%)
White	82 (75.9)	89 (84.0)	85 (82.5)	84 (77.8)	83 (84.7)	81 (84.4)	81 (82.7)	112 (69.6)	114 (68.7)	109 (65.3)
Black	6 (5.6)	2 (1.9)	6 (5.8)	6 (5.6)	11 (11.2)	12 (12.5)	14 (14.3)	17 (10.6)	21 (12.7)	22 (13.2)
Asian	13 (12.0)	7 (6.6)	9 (8.7)	13 (12.0)	–	–	–	25 (15.5)	27 (16.3)	29 (17.4)
Other	7 (6.5)	8 (7.5)	3 (2.9)	5 (4.6)	4 (4.1)	3 (3.1)	3 (3.1)	7 (4.3)	4 (2.4)	7 (4.2)
BMI (kg/m^2), mean (SD)	25.7 (4.0)	26.4 (4.0)	25.8 (3.4)	25.9 (3.7)	32.1 (6.3)	32.3 (5.7)	33.2 (6.4)	27.6 (5.7)	27.3 (5.3)	27.4 (6.2)

Abbreviations: IHR, inguinal hernia repair; SD, standard deviation; TKA, total knee arthroplasty; BMI, body mass index.

Table 3 Measures of pain 72 hours postsurgery

	Post-IHR				Post-TKA			Posthysterectomy
	Pregabalin			Placebo	Pregabalin		Placebo	Pregabalin		Placebo
	50 mg/d	150 mg/d	300 mg/d		150 mg/d	300 mg/d		150 mg/d	300 mg/d
Worst pain	n=102	n=98	n=98	n=101	n=56	n=52	n=55	n=148	n=147	n=146
LS mean (SE)	4.2 (0.24)	4.3 (0.25)	3.9 (0.24)	4.2 (0.24)	6.32 (0.33)	5.98 (0.35)	5.96 (0.34)	5.0 (0.21)	5.0 (0.21)	5.0 (0.22)
Difference vs placebo	0.0 (0.33)	0.1 (0.33)	−0.3 (0.33)		0.36 (0.45)	0.01 (0.46)		−0.1 (0.28)	−0.1 (0.28)
95% CI	−0.7, 0.6	−0.6, 0.7	−0.9, 0.4		−.54, 1.25	−0.90, 0.92		−0.6, 0.5	−0.6, 0.5
P-value	0.880	0.774	0.409		0.431	0.978		0.827	0.858
Average pain	n=102	n=98	n=98	n=101	n=56	n=51	n=55	–	–	–
LS mean (SE)	2.5 (0.18)	2.5 (0.18)	2.4 (0.18)	2.5 (0.18)	4.28 (0.28)	3.74 (0.30)	4.19 (0.29)	–	–	–
Difference vs placebo	0.0 (0.24)	0.0 (0.24)	−0.1 (2.4)		0.09 (0.38)	−0.45 (0.39)		–	–
95% CI	−0.4, 0.5	−0.5, 0.5	−0.6, 0.4		−0.66, 0.85	−1.22, 0.33		–	–
P-value	0.858	0.968	0.710		0.806	0.26		–	–
Current pain	n=102	n=99	n=101	n=101	n=51	n=45	n=45	n=81	n=89	n=75
LS mean (SE)	2.5 (0.19)	2.7 (0.19)	2.2 (0.19)	2.3 (0.19)	3.97 (0.34)	3.27 (0.38)	3.83 (0.39)	2.15 (0.21)	1.79 (0.19)	2.35 (0.22)
Difference vs placebo	0.2 (0.25)	0.4 (0.25)	0.0 (0.25)		0.15 (0.48)	−0.56 (0.48)		−0.19 (0.28)	−0.55 (0.27)
95% CI	−0.2, 0.7	−0.1, 0.9	−0.5, 0.5		−0.80, 1.09	−1.51, 0.40		−0.73, 0.35	−1.08, −0.02
P-value	0.327	0.089	0.932		0.760	0.251		0.486	0.043

Abbreviations: CI, confidence interval; IHR, inguinal hernia repair; LS, least squares; SE, standard error; TKA, total knee arthroplasty.

Figure 3 Movement-related pain (numerical rated scale) at 1 hour, 2 hours, and 2 days post-IHR.

Notes: ^aP-value vs placebo <0.05; ^bP-value vs placebo <0.01. Data for 3 hours and Day 4, 5, 6, 7 postsurgery and at end of treatment not shown (all endpoints not significant).
Abbreviations: IHR, inguinal hernia repair; LS, least squares; NRS, numerical rated scale; SE, standard error.

Table 4 Cumulative total amount of opioids (oral morphine equivalents [mg])

	Post-IHR				Post-TKA			Posthysterectomy
	Pregabalin			Placebo	Pregabalin		Placebo	Pregabalin		Placebo
	50 mg/day	150 mg/d	300 mg/d		150 mg/d	300 mg/d		150 mg/d	300 mg/d
24 hours	n=102	n=99	n=101	n=101	n=85	n=86	n=84	n=150	n=147	n=153
LS mean (SE)	10.3 (2.3)	9.4 (2.3)	6.6 (2.3)	16.0 (2.3)	151.8 (14.2)	152.3 (14.3)	167.9 (14.6)	113.4 (7.1)	111.3 (7.2)	124.4 (7.2)
Difference vs placebo	−5.7 (3.1)	−6.6 (3.1)	−9.5 (3.1)		−16.1 (19.4)	−15.5 (19.4)		−11.1 (9.4)	−13.2 (9.5)
95% CI	−11.8, 0.3	−12.7, −0.5	−15.5, −3.4		−54.3, 22.2	−53.7, 22.7		−29.6, 7.5	−31.8, 5.5
P-value	0.063	0.035	0.002		0.409	0.423		0.241	0.165
48 hours	n=102	n=99	n=101	n=101	n=82	n=81	n=83	n=150	n=147	n=151
LS mean (SE)	13.2 (2.8)	14.1 (2.8)	9.7 (2.8)	19.8 (2.8)	86.4 (12.1)	93.9 (12.3)	122.8 (12.3)	148.7 (9.2)	145.0 (9.4)	168.3 (9.4)
Difference vs placebo	−6.6 (3.7)	−5.7 (3.8)	−10.1 (3.8)		−36.4 (16.5)	−29.0 (16.6)		−19.6 (12.3)	−23.4 (12.4)
95% CI	−14.0, 0.7	−13.1, 1.7	−17.4, −2.7		−69.0, −3.9	−61.6, 3.7		−43.8, 4.5	−47.7, 1.0
P-value	0.077	0.132	0.008		0.028	0.082		0.111	0.060
Week 1/dischargea	n=99	n=99	n=97	n=100	n=84	n=85	n=81	n=147	n=143	n=144
LS mean (SE)	15.9 (4.3)	22.2 (4.3)	16.2 (4.3)	28.2 (4.3)	36.2 (5.5)	48.4 (5.5)	39.4 (5.7)	164.28 (11.16)	167.01 (11.41)	195.32 (11.57)
Difference vs placebo	−12.3 (5.8)	−5.9 (5.8)	−12.0 (5.8)		−3.23 (7.5)	9.04 (7.5)		−31.04 (15.05)	−28.3 (15.14)
95% CI	−23.7, −0.9	−17.3, 5.5	−23.5, −0.5		−18.1, 11.6	−5.8, 23.8		−60.63, −1.45	−58.09, 1.46
P-value	0.035	0.309	0.041		0.669	0.230		0.040	0.062

Note:

a Week 1 for post-IHR at discharge for post-TKA and posthysterectomy.

Abbreviations: CI, confidence interval; IHR, inguinal hernia repair; LS, least squares; SE, standard error; TKA, total knee arthroplasty.

Table 5 Most common treatment-emergent adverse events (n [%], all-causality) in any treatment group in any trial

Events occurring in ≥10% of any treatment group	Post-IHR				Post-TKA			Posthysterectomy
	Pregabalin			Placebo	Pregabalin		Placebo	Pregabalin		Placebo
	50 mg/d	150 mg/d	300 mg/d		150 mg/d	300 mg/d		150 mg/d	300 mg/d
	n=108	n=106	n=103	n=108	n=98	n=96	n=98	n=161	n=166	n=167
Constipation	21 (19.4)	22 (20.8)	27 (26.2)	27 (25.0)	24 (24.5)	12 (12.5)	30 (30.6)	46 (28.6)	49 (29.5)	46 (27.5)
Nausea	21 (19.4)	18 (17.0)	14 (13.6)	22 (20.4)	29 (29.6)	31 (32.3)	51 (52.0)	67 (41.6)	60 (36.1)	76 (45.5)
Fatigue	24 (22.2)	18 (17.0)	23 (22.3)	23 (21.3)	20 (20.4)	15 (15.6)	19 (19.4)	38 (23.6)	46 (27.7)	34 (20.4)
Dizziness	15 (13.9)	20 (18.9)	29 (28.2)	16 (14.8)	20 (20.4)	25 (26.0)	16 (16.3)	51 (31.7)	52 (31.3)	37 (22.2)
Somnolence	24 (22.2)	25 (23.6)	25 (24.3)	28 (25.9)	24 (24.5)	22 (22.9)	20 (20.4)	39 (24.2)	39 (23.5)	36 (21.6)
Headache	5 (4.6)	3 (2.8)	1 (1.0)	3 (2.8)	7 (7.1)	3 (3.1)	9 (9.2)	27 (16.8)	23 (13.9)	19 (11.4)
Vomiting	2 (1.9)	7 (6.6)	1 (1.0)	7 (6.5)	14 (14.3)	15 (15.6)	25 (25.5)	33 (20.5)	20 (12.0)	30 (18.0)
Pyrexia	1 (0.9)	0 (0)	1 (1.0)	4 (3.7)	14 (14.3)	16 (16.7)	5 (5.1)	32 (19.9)	29 (17.5)	25 (15.0)
Insomnia	1 (0.9)	0 (0)	3 (2.9)	3 (2.8)	8 (8.2)	12 (12.5)	17 (17.3)	9 (5.6)	9 (5.4)	10 (6.0)
Pruritus	9 (8.3)	7 (6.6)	4 (3.9)	6 (5.6)	15 (15.3)	12 (12.5)	21 (21.4)	27 (16.8)	22 (13.3)	26 (15.6)
Hypotension	7 (6.5)	3 (2.8)	4 (3.9)	2 (1.9)	13 (13.3)	12 (12.5)	5 (5.1)	2 (1.2)	3 (1.8)	1 (0.6)
Disturbance in attention	11 (10.2)	11 (10.4)	15 (14.6)	16 (14.8)	10 (10.2)	11 (11.5)	11 (11.2)	24 (14.9)	30 (18.1)	23 (13.8)
Dysuria	10 (9.3)	6 (5.7)	10 (9.7)	10 (9.3)	5 (5.1)	4 (4.2)	5 (5.1)	14 (8.7)	22 (13.3)	17 (10.2)
Confusional state	6 (5.6)	3 (2.8)	8 (7.8)	6 (5.6)	9 (9.2)	10 (10.4)	5 (5.1)	12 (7.5)	12 (7.2)	9 (5.4)
Peripheral edema	0 (0)	0 (0)	0 (0)	1 (0.9)	8 (8.2)	9 (9.4)	11 (11.2)	4 (2.5)	1 (0.6)	1 (0.6)

Abbreviations: IHR, inguinal hernia repair; TKA, total knee arthroplasty.

Figure 4 Passive range of motion of the operated knee post-TKA.

Notes: Pregabalin 150 mg/d vs placebo; P<0.05 at 120 hours post-TKA. Pregabalin 300 mg/d vs placebo; P<0.01 at 72, 96, and 120 hours post-TKA. P<0.05 at 24 hours, at discharge, and at Week 4 post-TKA.
Abbreviations: LS, least squares; TKA, total knee arthroscopy.