Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials

Figures & data

Figure 1 Study flow diagram.

Table 1 Study design and subject disposition by study

Author, year	Drug, pain type	No of sites,a Countries	Opioid naive patients, n (%)	Patients enrolled in the OLP, n	Discontinued during OLP, %	OLP duration	Duration of study drug tapering	Patients randomized in each arm of RBTP, n	RBTP dosing regimen and duration	Post-randomization discontinuations, %	Concomitant analgesics allowed?	Rescue medication allowed?
Hale et al,^Citation14 2007	Oxymorphone ER, CLBP	30, USA	0 (0)	251	43	Up to 1 month	No taper (4-day extended access to rescue opioid)	Oxymorphone ER: 70 Placebo: 72	Fixed dose 12 weeks	Oxymorphone ER: 30 Placebo: 76	No	Yes
Katz et al,^Citation9 2007	Oxymorphone ER, CLBP	29, USA	205 (100)	326	37	Up to 1 month	No taper (4-day extended access to rescue opioid)	Oxymorphone ER: 105 Placebo: 100	Fixed dose 12 weeks	Oxymorphone ER: 32 Placebo: 53	Nob	Yes
Vorsanger et al,^Citation20 2008	Tramadol ER, CLBP	30, USA	Not stated	619	38	3 weeks	Not stated	Tramadol ER 300 mg: 127 Placebo: 126	Adjustable dose 12 weeks	Tramadol ER 300 mg: 33 Placebo: 48	No	Not stated
Hale et al,^Citation21 2010	OROS Hydromorphone ER, CLBP	66, USA	0 (0)	459	42	Up to 1 month	2 weeks	Hydromorphone ER: 133 Placebo: 133	Fixed dose 12 weeks	Hydromorphone ER: 51 Placebo: 68	No	Yes
Katz et al,^Citation22 2010	EMBEDA^®; MS-sNT (morphine sulfate and naltrexone hydrochloride ER capsules), OA	Not stated, USA	254 (73.8)	547	37	Up to 45 days	2 weeks	MS-sNT: 170 Placebo: 173	Fixed dose 12 weeks	MS-sNT: 36 Placebo: 43	No	Yes
Schwartz et al,^Citation23 2011	Tapentadol ER, DPNP	93, USA and Canada	255 (65.5)	588	33	3 weeks	3 days	Tapentadol ER: 196 Placebo: 193	Fixed dose 12 weeks	Tapentadol ER: 32 Placebo: 32	No	No
Friedmann et al,^Citation15 2011	Remoxy (Oxycodone ER), OA	61, USA	Not stated	558	26	2 weeks	Up to 15 days	Oxycodone ER: 203 Placebo: 207	Adjustable for first 4 weeks then fixed for 8 weeks Fixed dose 12 weeks	Oxycodone ER: 34 Placebo: 36	No	Not stated
Steiner et al,^Citation16 2011	Buprenorphine transdermal system (BTDS), CLBP	86, USA	541 (100)	1024	47	Up to 27 days	No taper	BTDS: 257 Placebo: 283	Fixed dose 12 weeks	BTDS: 33 Placebo: 30	No	Yes
Rauck et al,^Citation24 2014	Zohydro (Hydrocodone ER), CLBP	59, USA	0 (0)	510	41	Up to 6 weeks	2 weeks	Hydrocodone ER: 151 Placebo: 151	Fixed dose 12 weeks	Hydrocodone ER: 18 Placebo: 61	No	Yes
Vinik et al,^Citation25 2014	Tapentadol ER, DPNP	80, USA and Canada	218 (68.5)	459	22	3 weeks	3 days	Tapentadol ER: 166 Placebo: 152	Fixed dose 12 weeks	Tapentadol ER: 28 Placebo: 30	No	Yes
Wen et al,^Citation17 2015	Hysingla ER (Hydrocodone bitartrate ER), CLBP	102, USA	329 (56)	905	35	Up to 45 days	2 weeks	Hydrocodone ER: 296 Placebo: 292	Fixed dose 12 weeks	Hydrocodone ER: 23 Placebo: 28	No	Yes
Katz et al,^Citation18 2015	Xtampa ER (Oxycodone ER), CLBP	46, USA	192 (49.3)	740	47	Up to 6 weeks	Up to 20 days	Xtampa ER: 193 Placebo: 196	Fixed dose 12 weeks	Xtampa ER: 37 Placebo: 49	No	Yes
Hale et al,^Citation26 2015	Hydrocodone ER, CLBP/OA	71, USA	147 (50)	389	24	Up to 6 weeks	2 weeks	Hydrocodone ER: 146 Placebo: 147	Fixed dose 12 weeks	Hydrocodone ER: 36 Placebo: 31	Yes	Yes
Hale et al,^Citation27 2015	Hydrocodone ER, CLBP	78, USA	215 (58)	625	41	Up to 6 weeks	2 weeks	Hydrocodone ER: 191 Placebo: 180	Fixed dose 12 weeks	Hydrocodone ER: 18 Placebo: 21	Not stated	Yes
Rauck et al,^Citation28 2016	Buccal buprenorphine, CLBP	60, USA	420 (100)	749	39	Up to 8 weeks	No taper	Buccal Buprenorphine: 209 Placebo: 211	Fixed dose 12 weeks	Buccal Buprenorphine: 24 Placebo: 25	No	Yes

Notes:

a Number of sites initiated.

b Concomitant analgesics were not allowed during the dosed titration. The paper does not state anything about concomitant analgesics for the period following this.

Abbreviations: CLBP, chronic low back pain; DPNP, diabetic peripheral neuropathic pain; ER, extended release; OA, osteoarthritis; OLP, open label phase; RBTP, randomized blinded treatment phase.

Figure 2 Change in PI from randomization baseline to week 12 with active study opioid drug versus placebo.

Notes: The standardized mean difference effect size was −0.416 and p<0.001, with a lower bound estimate of −0.521 and an upper bound −0.312.
Abbreviation: PI, pain intensity.

Figure 3 Percentage of patients with ≥30% or ≥50% improvement with active study drug versus placebo.

Notes: The graph shows the mean (SD) percent of patients with improvement, from each study that reported these data. A binary random-effects meta-analysis using the restricted maximum likelihood method was performed showing a statistically significant difference between active study drug and placebo for both ≥30% and ≥50%.

Table 2 Summary of secondary endpoints

Secondary endpoint	Study drug vs placeboa	p-value
Responder rate for ≥30% improvement	0.166 (0.028)	<0.001
Responder rate for ≥50% improvement	0.137 (0.022)	<0.001
PGIC (“Very much improved” and “Improved”)	0.163 (0.029)	<0.001
PGASM (“Excellent” and “Very good”)	0.194 (0.056)	<0.001
Patients discontinued due to an AE	0.021 (0.008)	0.011

Note:

a Values are the risk difference (RD) estimates (SE).

Abbreviations: AE, adverse event; PGASM, patient global assessment of study medication; PGIC, patient global impression of pain; SE, standard error.

Table 3 Summary of AEs

Reference	Study drug/placebo	Patients with ≥1 AE, n (%)	Patients with ≥1 SAE, n (%)	Patients who discontinued due to an AE, n (%)	Patients who discontinued due to opioid withdrawal, n (%)
Hale et al,^Citation14 2007	Study drug:	31 (44.3)	2 (2.9)	7 (10.0)	0 (0.0)
	Placebo:	27 (37.5)	0 (0.0)	8 (11.1)	5 (6.9)
Katz et al,^Citation9 2007	Study drug:	61 (58.1)	2 (1.9)	9 (8.6)	1 (1.0)
	Placebo:	44 (44.0)	3 (3.0)	8 (8.0)	2 (2.0)
Vorsanger et al,^Citation20 2008a	Study drug:	79 (62.2)	ND	13 (10.2)	ND
	Placebo:	72 (57.1)	ND	18 (14.3)	ND
Hale et al,^Citation21 2010	Study drug:	64 (48.1)	1 (0.8)	7 (5.3)	3 (2.3)
	Placebo:	73 (54.9)	4 (3.0)	3 (2.3)	7 (5.3)
Katz et al,^Citation22 2010	Study drug:	91 (53.2)	6 (3.5)	18 (10.6)	ND
	Placebo:	84 (48.6)	3 (1.7)	13 (7.5)	ND
Schwartz et al,^Citation23 2011	Study drug:	139 (70.9)	10 (5.1)	22 (11.2)	ND
	Placebo:	100 (51.8)	3 (1.6)	11 (5.7)	ND
Friedmann et al,^Citation15 2011	Study drug:	ND	5 (2.4)	43 (21.0)	ND
	Placebo:	ND	ND	ND	ND
Steiner et al,^Citation16 2011	Study drug:	140 (54.5)	3 (1.2)	40 (15.6)	ND
	Placebo:	146 (51.6)	2 (0.7)	20 (7.1)	ND
Rauck et al,^Citation24 2014	Study drug:	91 (60.3)	ND	2 (1.3)	0 (0.0)
	Placebo:	67 (44.4)	ND	5 (3.3)	7 (4.6)
Vinik et al,^Citation25 2014	Study drug:	23 (13.9)	8 (4.8)	19 (11.4)	4 (2.4)
	Placebo:	13 (8.6)	9 (5.9)	12 (7.9)	5 (3.3)
Wen et al,^Citation17 2015	Study drug:	136 (45.9)	2 (0.7)	17 (5.7)	ND
	Placebo:	103 (35.3)	4 (1.4)	10 (3.4)	ND
Katz et al,^Citation18 2015	Study drug:	125 (64.8)	2 (1.0)	15 (7.8)	3 (1.6)
	Placebo:	95 (48.5)	2 (1.0)	10 (5.1)	1 (0.5)
Hale et al,^Citation26 2015	Study drug:	93 (63.7)	3 (2.1)	9 (6.2)	ND
	Placebo:	95 (48.5)	2 (1.0)	10 (5.1)	1 (0.5)
Hale et al,^Citation27 2015	Study drug:	106 (55)	3 (1.6)	11 (5.8)	ND
	Placebo:	88 (49)	3 (1.7)	7 (3.9)	ND
Rauck et al,^Citation28 2016	Study drug:	38 (16.6)	3 (1.4)	13 (5.7)	3 (1.3)
	Placebo:	40 (17.2)	1 (0.5)	7 (3.0)	1 (0.4)

Notes:

a Only data for the 300 mg doses of tramadol were used in this meta-analysis.

Abbreviations: AE, adverse event; ND, no data; SAE, serious AE.

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