Study Design Characteristics and Endpoints for Enriched Enrollment Randomized Withdrawal Trials for Chronic Pain Patients: A Systematic Review

Figures & data

Figure 1 Design of enrichment enrolment withdrawal trials.

Figure 2 PRISMA flow diagram.

Abbreviations: n, number; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1 Characteristics of EERW Pain Trials with NRS or VAS as Primary Endpoint

Author, Year	Drug	Pain Type	Sites (n)	Pt (n) Screened	Pt (n) in SP	Pt (n) in DB, % Pt of SP	Duration SP (wk)	Duration DB (wk)	Primary Endpoint	Time to LTR as Secondary Endpoint
Rauck,^Citation17 2016	Buccal buprenorphine	CLBP	60	1633	749	461, 62%	≤8	12	NRS	NR
Gimbel,^Citation18 2016	Buccal buprenorphine	CLBP	66	1656	815	511, 63%	8	12	NRS	NR
Rauck,^Citation19 2015	Oxycodone ER + NLX	CLBP	47	663	410	281, 69%	≤6	12	NRS	A) Discontinuation due to lack of efficacy B) 30% & 50% loss of analgesia
Katz,^Citation20 2015	Oxycodone ER	CLBP	46	NS	740	389, 53%	4	12	NRS	Discontinuation for any reason
Hale,^Citation21 2015	Hydrocodone ER	CLBP	87	845	625	370, 59%	4 to 6	12	NRS	Discontinuation due to lack of efficacy or excessive use of RM
Hale,^Citation22 2015	Hydrocodone ER	CLBP/OA	73	519	389	294, 76%	6	12	NRS	>33% & >50% pain increase at wk 1,2,4,8,12
Wen,^Citation23 2015	Oxycodone	CLBP	94	1927	905	588, 65%	7	12	NRS	NR
Raskin,^Citation24 2014	Pregabalin	PDN	258	1105	665	294, 44%	6	13	NRS	<15% pain relief compared with SP baseline
Vinik,^Citation25 2014	Tapentadol	PDN	80	917	459	320, 70%	3	12	NRS	NR
Rauck,^Citation26 2014	Hydrocodone ER	CLBP	59	828	510	302, 59%	6	12	NRS	Discontinuation due to lack of efficacy
Toth,^Citation27 2012	Nabilone	PDN	1	51	37	26, 70%	4	5	NRS	NR
Steiner,^Citation28 2011	Buprenorphine patch	CLBP	86	1466	1024	541, 53%	4	12	NRS	Discontinuation due to lack of efficacy
Schwartz,^Citation29 2011	Tapentadol	PDN	87	1131	588	395, 67%	3	12	NRS	NR
Gilron,^Citation30 2011	Pregabalin	PDN/PHN	25	405	256	157, 61%	4	5	NRS	Discontinuation or pain increase of ≥1 on NRS and <30% difference from SP baseline
Hale,^Citation31 2010	Hydromorphone ER	CLBP	66	806	459	268, 58%	2 to 4	12	NRS	Discontinuation due to lack of efficacy, AEs or use of RM
Katz,^Citation32 2010	Morphine + NLX	OA	77	NR	547	344, 63%	6.5	12	NRS	Discontinuation for any reason
Katz,^Citation33 2007	Oxymorphone	CLBP	29	NR	325	205, 63%	NS	12	VAS	A) Discontinuation due to lack of efficacy B) Discontinuation for any reason
Hale,^Citation34 2007	Oxymorphone ER	CLBP	31	NR	250	143, 57%	NS	12	VAS	Discontinuation due to lack of efficacy
Caldwell,^Citation35 1999	Oxycodone CR	OA	9	NR	167	107, 64%	4	4	4p NRS	NR

Abbreviations: 4p, 4 point; AEs, adverse events; CLBP, chronic low back pain; CR, controlled release; DB, double-blind phase; ER, extended release; LTR, loss of therapeutic response; n, number; NLX, naltrexone; NR, not reported; NRS, 11-point numerical rating scale; OA, osteoarthritis; PDN, painful diabetic neuropathy; PHN, post herpetic neuralgia; Pt, patients; RM, rescue medication; SP, selection phase; VAS, visual analogue scale; wk, week.

Table 2 Characteristics of EERW Pain Trials with Time to LTR & Treatment Failure as Primary Endpoint

Author, Year	Drug	Pain Type	Sites (n)	Patients Screened (n)	Patients in SP (n)	Patients in DB (n), % pt of SP	Duration SP (wk)	Duration DB (wk)	Primary Endpoint Time to LTR	NRS (Change) Reported
Kawamata,^Citation36 2019	Oxycodone ER	CLBP	54	NR	188	130, 69%	4	5	1) <MPR30 or >3 on NRS for 3 consecutive days, or 2) worsening leading to dose increase, change or addition of analgesic, including RM	Yes
Huffman,^Citation37 2017	Pregabalin CR	PHN	116	1117	801	413, 52%	6	13	1) <MPR30, or 2) discontinuation due to AE or lack of efficacy	Yes
Arai,^Citation38 2015	Fentanyl patch	CLBP/OA	59	240	218	150, 69%	1 to 4	12	1) >15 VAS during 3 consecutive days compared to last 3 days of SP, 2) mean >1/day RM for 3 days compared to last 3 days of SP, 3) ≥3/day RM for 5 days, 4) discontinuation due to lack of efficacy, or 5) dose increase	Yes
Arai,^Citation38 2015	Fentanyl patch	PHN/CRPS/CPOP	90	280	258	163, 63%	1 to 4	12
Arnold,^Citation39 2014	Pregabalin CR	FM	50	770	441	122, 28%	6	13	1) <MPR30, or 2) discontinuation due to AE or lack of efficacy	Yes
Clauw,^Citation40 2013	Milnacipran	FM	58	358	340	151, 44%	4	12	1) <MPR30 at visit, or 2) worsening requiring alternative treatment, as judged by the trial’s principal investigator	No
Baron,^Citation41 2010	Pregabalin	LSRP	46	544	378	217, 57%	4	5	1) <MPR30 (mean weekly) and ≥1 on NRS, 2) use of RM, or 3) discontinuation	Yes
Crofford,^Citation42 2008	Pregabalin	FM	95	1777	1051	566, 54%	6	26	1) <MPR30 at 2 consecutive visits (the first of the 2 visits defined the time to LTR), or 2) worsening requiring alternative treatment, as judged by the trial’s principal investigator	No
Zakrzewska,^Citation43 2017	Raxatrigine	TN	25	125	67	29, 43%	3	4	Treatment failure: 1) >3 paroxysms in 1 wk and 2) ≥50% intensity or ≥50% frequency	Yes

Abbreviations: AE, adverse event; CLBP, chronic low back pain; CPOP, chronic post-operative pain; CR, controlled release; CRPS, complex regional pain syndrome; DB, double-blind phase; ER, extended release; FM, fibromyalgia; LSRP, lumbosacral radiculopathy; LTR, loss of therapeutic response; MPR30, minimum pain relief of 30% compared to selection phase baseline pain score; n, number; NRS, 11-point numerical rating scale; NR, not reported; OA, osteoarthritis; PHN, post herpetic neuralgia; pt, patients; RM, rescue medication; SP, selection phase; TN, trigeminal neuralgia; VAS, 100 mm visual analogue scale; wk, week.

Figure 3 Risk of bias summary.

Abbreviations: L, chronic low back pain; LO, chronic low back pain and osteoarthritis; NP, neuropathic pain.

Table 3 Effect Sizes and Treatment-Emergent Adverse Events in the Double-Blind Phase

Author, Year	Absolute Effect Size^a	95% CI	Standardized Effect Size^b	95% CI	MPR30 Act.	MPR30 Plac.	MPR50 Act.	MPR50 Plac.	NNT	TEAE Act.	TEAE Plac.
Rauck,^Citation17 2016	−0.67	−1.07 to −0.26	−0.334	−0.526 to −0.141	63%*	47%	41%	33%	12.5	41.0%	43.5%
Gimbel,^Citation18 2016	−0.98	−1.32 to −0.64	−0.569	−0.750 to −0.389	64%*	31%	40%*	17%	4.4	49.2%	49.2%
Rauck,^Citation19 2015	−0.62	−1.11 to −0.01	−0.321	−0.557 to −0.086	58%*	44%	40%	30%	10.2	56.8%	56.0%
Katz,^Citation20 2015	−1.56	−2.10 to −1.10	−0.593	−0.796 to −0.390	49%*	33%	38%*	25%	7.2	64.8%	48.5%
Hale,^Citation21 2015	−0.63	−1.00 to −0.26	−0.320	−0.525 to −0.115	NR	NR	NR	NR	NC	49.1%	55.5%
Hale,^Citation22 2015	−0.36	NR	NC	NC	NR	NR	NR	NR	NC	63.7%	61.9%
Wen,^Citation23 2015	−0.53	−0.88 to −0.18	NC	NC	65%*	53%	48%*	39%	11.1	45.9%	35.3%
Raskin,^Citation24 2014^§	NR	NR	NC	NC	83%	79%	63%	55%	13.2	61.2%	64.6%
Vinik,^Citation25 2014	−0.95	−1.42 to −0.49	−0.456	−0.679 to −0.234	55%*	45%	40%*	29%	8.7	79.5%	61.2%
Rauck,^Citation26 2014	−0.48	NR	−0.308	−0.535 to −0.081	68%*	31%	48%*	23%	4.1	60.0%	44.0%
Toth,^Citation27 2012^§	−1.27	−2.29 to −0.25	NC	NC	85%*	38%	31%	8%	4.3	53.8%	46.2%
Steiner,^Citation28 2011	−0.58	−1.02 to −0.14	NC	NC	53%	46%	44%	36%	12.5	54.7%	55.1%
Schwartz,^Citation29 2011	−1.30	−1.70 to −0.92	−0.674	−0.878 to-0.469	54%*	42%	38%*	28%	9.8	70.9%	51.8%
Gilron,^Citation30 2011^§	−0.78	−1.27 to −0.30	NC	NC	NR	NR	NR	NR	NC	71.4%	60.0%
Hale,^Citation31 2010	−1.40	NR	NC	NC	61%*	43%	42%*	24%	5.5	47.8%	54.5%
Katz,^Citation32 2010	−0.50	NR	−0.250	−0.463 to −0.038	73%*	58%	57%	47%	10.8	53.2%	48.6%
Katz,^Citation33 2007	−1.69	−2.37 to −1.01	−0.694	−0.976 to −0.412	63%*^3	34%^c	58%*^c	26%^c	3.1	58.1%	44.0%
Hale,^Citation34 2007	−2.30	NR	NC	NC	NR	NR	NR	NR	NC	44.3%	37.5%
Kawamata,^Citation36 2019	−0.40	NR	−0.248	−0.594 to 0.097	NR	NR	NR	NR	NR	72.6%	54.4%
Huffman,^Citation37 2017^§	−1.00	−1.34 to −0.65	NC	NC	96%*	84%	88%*	69%	5.3	38.5%	30.7%
Arai,^Citation38 2015	−0.73	−1.35 to −0.11	−0.363	−0.686 to −0.041	NR	NR	NR	NR	NC	68.5%	46.8%
Arai,^Citation38 2015	−0.87	−1.50 to −0.024	−0.475	−0.786 to −0.163	NR	NR	NR	NR	NC	85.7%	70.9%
Arnold,^Citation39 2014^§	−0.60	NR	NC	NC	68%	59%	47%	40%	14.1	79.4%	67.2%
Clauw,^Citation40 2013	NR	NR	NC	NC	NR	NR	NR	NR	NC	47.0%	58.0%
Baron,^Citation41 2010^§	−0.21	NR	NC	NC	NR	NR	NR	NR	NC	40.9%	42.1%
Crofford,^Citation42 2008	NR	NR	NC	NC	NR	NR	NR	NR	NC	61.6%	44.9%
Zakrzewska,^Citation43 2017	−2.31	−3.78 to −0.83	NC	NC	NR	NR	60%	14%	2.2	26.7%	35.7%

Notes:^aThe absolute effect size is presented as reported by the original authors and often is not the crude absolute effect, but an adjusted estimate. VAS is transformed into NRS;^bThe standardized effect size is calculated from the crude data and is thus not adjusted for baseline NRS, VAS or other covariates;^cRecalculated percentages, including drop-outs instead of trial completers; ^§Single-blind selection phase; * P < 0.05 compared with placebo.

Abbreviations: Act., active group; CI, confidence interval; NC, not calculable because of missing data such as standard deviations; NNT, numbers needed to treat calculated from MPR50 raw data; NR, not reported; MPR30 or MPR50, minimum pain relief of 30% or 50%, from selection phase baseline pain score to end of double-blind phase; Plac., placebo group; TEAE, treatment-emergent adverse events.

Figure 4 Funnel plot of effect sizes.

Abbreviation: REML, restricted maximum likelihood.

Figure 5 Relation between double-blind baseline NRS and absolute effect size.

Abbreviation: NRS, 11-point numerical rating scale.

Rauck RL, Potts J, Xiang Q, Tzanis E, Finn A. Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain. Postgrad Med. 2016;128(1):1–11. doi:10.1080/00325481.2016.1128307

 PubMed Web of Science ®Google Scholar

Gimbel J, Spierings EL, Katz N, Xiang Q, Tzanis E, Finn A. Efficacy and tolerability of buccal buprenorphine in opioid-experienced patients with moderate to severe chronic low back pain: results of a Phase 3, enriched enrollment, randomized withdrawal study. Pain. 2016;157(11):2517–2526. doi:10.1097/j.pain.0000000000000670

 PubMed Web of Science ®Google Scholar

Rauck RL, Hale ME, Bass A, et al. A randomized double-blind, placebo-controlled efficacy and safety study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) for moderate-to-severe chronic low back pain treatment. Pain. 2015;156(9):1660–1669. doi:10.1097/j.pain.0000000000000230

 PubMed Web of Science ®Google Scholar

Katz N, Kopecky EA, O’Connor M, Brown RH, Fleming AB. A phase 3, multicenter, randomized, double-blind, placebo-controlled, safety, tolerability, and efficacy study of Xtampza ER in patients with moderate-to-severe chronic low back pain. Pain. 2015;156(12):2458–2467. doi:10.1097/j.pain.0000000000000315

 PubMed Web of Science ®Google Scholar

Hale ME, Zimmerman TR, Eyal E, Malamut R. Efficacy and safety of a hydrocodone extended-release tablet formulated with abuse-deterrence technology in patients with moderate-to-severe chronic low back pain. J Opioid Manag. 2015;11(6):507–518. doi:10.5055/jom.2015.0304

 PubMedGoogle Scholar

Hale ME, Laudadio C, Yang R, Narayana A, Malamut R. Efficacy and tolerability of a hydrocodone extended-release tablet formulated with abuse-deterrence technology for the treatment of moderate-to-severe chronic pain in patients with osteoarthritis or low back pain. J Pain Res. 2015;8:623–636. doi:10.2147/JPR.S83930

 PubMed Web of Science ®Google Scholar

Wen W, Sitar S, Lynch SY, He E, Ripa SR. A multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of single-entity, once-daily hydrocodone tablets in patients with uncontrolled moderate to severe chronic low back pain. Expert Opin Pharmacother. 2015;16(11):1593–1606. doi:10.1517/14656566.2015.1060221

 PubMed Web of Science ®Google Scholar

Raskin P, Huffman C, Toth C, et al. Pregabalin in patients with inadequately treated painful diabetic peripheral neuropathy: a randomized withdrawal trial. Clin J Pain. 2014;30(5):379–390. doi:10.1097/AJP.0b013e31829ea1a1

 PubMed Web of Science ®Google Scholar

Vinik AI, Shapiro DY, Rauschkolb C, et al. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care. 2014;37(8):2302–2309. doi:10.2337/dc13-2291

 PubMed Web of Science ®Google Scholar

Rauck RL, Nalamachu S, Wild JE, et al. Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study. Pain Med. 2014;15(6):975–985. doi:10.1111/pme.12377

 PubMed Web of Science ®Google Scholar

Toth C, Mawani S, Brady S, et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain. 2012;153(10):2073–2082. doi:10.1016/j.pain.2012.06.024

 PubMed Web of Science ®Google Scholar

Steiner DJ, Sitar S, Wen W, et al. Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study. J Pain Symptom Manage. 2011;42(6):903–917. doi:10.1016/j.jpainsymman.2011.04.006

 PubMed Web of Science ®Google Scholar

Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151–162. doi:10.1185/03007995.2010.537589

 PubMed Web of Science ®Google Scholar

Gilron I, Wajsbrot D, Therrien F, Lemay J. Pregabalin for peripheral neuropathic pain: a multicenter, enriched enrollment randomized withdrawal placebo-controlled trial. Clin J Pain. 2011;27(3):185–193. doi:10.1097/AJP.0b013e3181fe13f6

 PubMed Web of Science ®Google Scholar

Hale M, Khan A, Kutch M, Li LS. Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain. Curr Med Res Opin. 2010;26(6):1505–1518. doi:10.1185/03007995.2010.484723

 PubMed Web of Science ®Google Scholar

Katz N, Hale M, Morris D, Stauffer J. Morphine sulfate and naltrexone hydrochloride extended release capsules in patients with chronic osteoarthritis pain. Postgrad Med. 2010;122(4):112–128. doi:10.3810/pgm.2010.07.2179

 PubMed Web of Science ®Google Scholar

Katz N, Rauck R, Ahdieh H, et al. A 12-week, randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain. Curr Med Res Opin. 2007;23(1):117–128. doi:10.1185/030079906X162692

 PubMed Web of Science ®Google Scholar

Hale ME, Ahdieh H, Ma T, Rauck R. Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe chronic low back pain in opioid-experienced patients: a 12-week, randomized, double-blind, placebo-controlled study. J Pain. 2007;8(2):175–184. doi:10.1016/j.jpain.2006.09.011

 PubMed Web of Science ®Google Scholar

Caldwell JR, Hale ME, Boyd RE, et al. Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus Acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial. J Rheumatol. 1999;26(4):862–869.

 PubMed Web of Science ®Google Scholar

Kawamata M, Iseki M, Kawakami M, et al. Efficacy and safety of controlled-release oxycodone for the management of moderate-to-severe chronic low back pain in Japan: results of an enriched enrollment randomized withdrawal study followed by an open-label extension study. J Pain Res. 2019;12:363–375. doi:10.2147/JPR.S179110

 PubMed Web of Science ®Google Scholar

Huffman CL, Goldenberg JN, Weintraub J, et al. Efficacy and safety of once-daily controlled-release pregabalin for the treatment of patients with postherpetic neuralgia: a double-blind, enriched enrollment randomized withdrawal, placebo-controlled trial. Clin J Pain. 2017;33(7):569–578. doi:10.1097/AJP.0000000000000445

 PubMed Web of Science ®Google Scholar

Arai T, Kashimoto Y, Ukyo Y, Tominaga Y, Imanaka K. Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naive patients with chronic pain. Curr Med Res Opin. 2015;31(12):2207–2218. doi:10.1185/03007995.2015.1092127

 PubMed Web of Science ®Google Scholar

Arnold LM, Arsenault P, Huffman C, et al. Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a Phase III, double-blind, randomized withdrawal, placebo-controlled study. Curr Med Res Opin. 2014;30(10):2069–2083. doi:10.1185/03007995.2014.928275

 PubMed Web of Science ®Google Scholar

Clauw DJ, Mease PJ, Palmer RH, Trugman JM, Wang Y. Continuing efficacy of milnacipran following long-term treatment in fibromyalgia: a randomized trial. Arthritis Res Ther. 2013;15(4):R88. doi:10.1186/ar4268

 PubMed Web of Science ®Google Scholar

Baron R, Freynhagen R, Tölle TR, et al. The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy. Pain. 2010;150(3):420–427. doi:10.1016/j.pain.2010.04.013

 PubMed Web of Science ®Google Scholar

Crofford LJ, Mease PJ, Simpson SL, et al. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain. 2008;136(3):419–431. doi:10.1016/j.pain.2008.02.027

 PubMed Web of Science ®Google Scholar

Zakrzewska JM, Palmer J, Morisset V, et al. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol. 2017;16(4):291–300. doi:10.1016/S1474-4422(17)30005-4

 PubMed Web of Science ®Google Scholar