Chronic Pain Treatment With Opioid Analgesics

Benefits versus Harms of Long-term Therapy

Nalini Sehgal; James Colson; Howard S Smith

Expert Rev Neurother. 2013;13(11):1201-1220.

Conclusions

CNCP treatments are far from optimal. As a result, many CNCP patients experience poorly controlled pain and its deleterious effects for years. Ideally, effective treatment for CNCP should provide clinically significant pain relief that is sustained over years and improves physical activity, sleep, mood and QoL in the majority of cases. The burden of treatment related adverse effects should be small so that compliance with treatment remains high. Judging by these criteria, it is obvious that opioid therapy for CNCP is not a universal success. Controlled clinical trials show that 50–70% patients with CNCP fail opioid therapy. Those who respond, report mild to moderate reduction in pain intensity for a short term. There is no controlled study on opioid efficacy which is longer than 16 weeks in duration. In practice, long-term efficacy is extrapolated from short duration studies, which is obviously problematic and misleading. Uncontrolled prospective studies with follow-up intervals of 6–24 months, show that majority of patients who initially respond to opioids ultimately abandon treatment, either due to declining efficacy or troublesome side effects. The evidence on functional status is even less convincing: there is a lack of studies showing that opioids improve physical activity, function, sleep, mood or QoL. Very few studies have measured functional outcomes and those that do, vary in the selection of specific outcomes and assessment tools. There is no evidence that opioids decrease depression, anxiety, physical disability or increase return to work rates among disabled CNCP patients. There is a high prevalence of depression and anxiety in CNCP patients, and patients with psychiatric comorbidity are more likely to receive opioids. Yet such patients are excluded from opioid efficacy randomized clinical trials. Hence, the results of such trials lack generalizability to the majority of CNCP population. Opioid therapy is also associated with multiple side effects, and 80% patients experience more than one side effect. Among these, constipation is particularly troublesome and can become a serious problem for some patients. Endocrine disturbances, reported previously in heroin addicts, are not rare in CNCP patients on long-acting opioids. Furthermore, opioid therapy is not free from risk of addiction, as was once believed. CP patients with psychiatric comorbidity and personal or family history of current or past substance abuse are at increased risk for opioid misuse. Opioid misuse, abuse, overdose and unintentional death rates have trended upwards with liberal use of opioids in past two decades. Opioid related mortality rates are dose dependent, the rates increase manifold at higher doses. Although there is no consensus yet on an upper dose limit for opioids, studies suggest an optimal balance, where the benefits outweigh risk is achieved at doses of <100 mg/day MED.

So, 'do the benefits of opioid therapy outweigh the risks in CNCP?' Current evidence suggests that a balance, where the greatest amount of pain and related suffering is mitigated and there is the least amount of opioid related adverse effects, is difficult to achieve in the vast majority of CNCP patients. At the same time, there is a need to be mindful of the widespread and adverse consequences of poorly managed pain itself. Therefore, opioids should be considered only when pain is severe and other non-opioid therapies fail to adequately control pain. A structured approach that includes a bio-psychosocial evaluation should be employed when considering initiation or continuation of opioid therapy for a patient with chronic nonterminal pain. Opioids should be prescribed on a trial basis, and continued only if progress toward functional goals is demonstrated. Proper patient screening, education and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Specialist consultation should be sought for patients on high doses, and with complex psychiatric and social issues. Identifying patients who are more likely to respond to long-term opioid therapy is a challenge. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy.^[137] In general, a patient with stable psychosocial status and nociceptive pain, responsive to low to moderate doses of opioids, has a greater chance of success with long-term opioid therapy than a patient with a complex and unstable psychosocial background and neuropathic pain only partly relieved by high doses of potent opioid analgesics. In addition, treatment in a multidisciplinary setting versus solo practise improves compliance and decreases risk of abuse and complications. The evidence for this type of pain management is however meager and studies that compare treatment outcomes in multidisciplinary versus single modality treatments are needed. Presently, a 'trial and error' method is employed to identify patients with opioid responsive pain. Such an approach is costly, time consuming and inefficient and needs to be replaced by objective bedside clinical or laboratory tests that can reliably prognosticate treatment response to opioids. Research on drug development should direct, efforts at discovering drugs that retain the analgesic potency of opioids without their addictive potential. Drugs that bind to opioid receptors in the inflamed or injured tissues or PNS and do not enter the CNS, may be associated with lower risk of adverse effects and lower abuse potential. Finally, there is need for a research strategy to study long-term opioid effectiveness, identify and quantify adverse effects and improve evidence generation methodology.^[140]

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Table 1. Opioid efficacy randomized controlled trials of ≥12 weeks' duration.
Study (year)	Study duration (weeks)	Pain condition and sample size (n)	Drug, dose/day (mg)	Pain relief	Function	Treatment discontinued	Ref.
Jamison et al. (1998 )	16 (RCT) & 16 (open label)	Chronic LBP n = 36	Oxycodone 20 mg (fixed dose) versus ER morphine + oxycodone (titrated dose, maximum allowed 200 mg) versus naproxen	+	+ No validated function tools	Due to AE: 3/36	[33]
Babul et al.(2004)	12	OA knee n = 246	Tramadol ER (100–400 mg/day) versus placebo	+	+	27%	[54]
Markenson et al. (2005)	12.8 (90 days)	OA n = 107	Oxycodone CR versus placebo	+	+	Not reported	[66]
Gana et al. (2006)	12	OA knee or hip n = 1020	Tramadol ER daily 100, 200, 300, 400 versus placebo	+	+ (WOMAC)	Not reported	[141]
Katzet al. (2007)	12 Enriched enrollment	Chronic LBP n = 205	Oxymorphone versus placebo	+	Not reported	D/C due to AE: 18% (during titration) & 8% (later in each gp) LOE: 1% completed: 68 versus 47% (oxymorphone vs placebo)	[56]
Burch et al.(2007)	12	OA knee n = 646	Tramadol contramid (200–300 mg/day) versus placebo	+	Not reported	32% in tramadol gp	[57]
Hale et al. (2007)	12 Enriched enrollment	Ch LBP n = 143	Oxymorphone ER (20–260 mg, median 60 mg) versus placebo	+	Not reported	Total: 30% Due to LOE: 11%	[58]
Hanna et al.(2008)	12	DPN n = 338	Gabapentin (1200–1800 mg/day) + oxycodone (10–80 mg/day) versus gabapentin (1200–1800 mg/day) + placebo	+ Superior pain relief in G + O gp versus G alone	Not reported	64% in oxycodone gp D/C rates lower in G + O	[142]
Vorsanger et al. (2008)	15 (3 open label; & 12 RCT w/o washout)	Ch LBP n = 619 (open) 386 (randomized)	Tramadol ER 200 mg versus 300 mg versus placebo	+	Not reported	38% in tramadol gp	[34]
Vondrackova et al. (2008)	12	Ch LBP n = 463	Oxycodone PR-naloxone (10/5 or 20/10 mg) versus oxycodone PR (10 or 20 mg) versus placebo	+	Not reported	11.9% Oxy PR 11.69% oxycodone PR-naloxone	[59]
Afilalo et al. (2010)	15	OA n = 1023	Tapentadol ER 100–250 mg b.i.d. versus oxycodone CR 20–50 mg b.i.d. versus placebo	+	Not reported	Tapentadol 19.2% [66/34] Oxycodone 43.0% [147/342] higher d/c rate due to LOE (placebo), AE (opioid)	[35]
Buynak et al. (2010)	15	Chronic LBP n = 981	Tapentadol ER 100–250 mg b.i.d. versus oxycodone CR 20–50 mg b.i.d. versus placebo	+	Not reported	52% tapentadol, 47% placebo, 40% oxycodone gp completed study	[143]
DeLemos et al. (2011)	12	OA hip or knee n = 1001	Tramadol ER (100, 200, 300 mg) versus celecoxib (200 mg) versus placebo	+/-	WOMAC	Not reported	[37]
Schwartz et al. (2011)	15 Enriched enrollment	DPN n = 395	Tapentadol ER 100–250 mg b.i.d. versus placebo	+ 30% pain relief at 12 weeks	Not reported	Not reported	[36]

AE: Adverse effect; D/C: Discontinue; DPN: Diabetic polyneuropathy; LOE: Loss of effect; LBP: Low back pain; OA: Osteoarthritis; RCT: Randomized controlled trial; WOMAC: Western Ontario & McMaster Universities Osteoarthritis Index.

Table 2. Opioid efficacy prospective uncontrolled trials of ≥12 weeks' duration.
Study (year)	Study duration	Pain condition & sample size	Drug, dose/day (mg)	Pain relief	Function	Treatment discontinued	Ref.
Roth et al.(2000)	Extension trial 18 months (2 weeks RCT)	OA pain >1 month n = 106	Oxycodone Cr 20 mg versus oxycodone CR 40 mg versus placebo	+ 20% or > decrease from baseline pain	Not significant Activity & lifestyle questionnaire	In first 2 weeks (RCT phase): 52.6% Long term: 56.6%	[40]
Allan et al. (2005)	Open-label comparison study 13 months	Chronic LBP n = 680	Transdermal fentanyl (25–50 μg/h) versus SR morphine (60–140 mg/day)	+	Not reported	Fentanyl 37% versus morphine 31%	[55]
Agarwal et al.(2007)	Open label 16 weeks	Neuropathic pain (neuropathy, DPN, post-amputation) n = 53	Transdermal fentanyl (25–150 μg/h) Average dose: 105.6 μg/h	+	+ activity measured on actigraph	13/53 withdrew at varying time	[45]
Portenoy et al. (2007)	Open-label 3-year registry; terminated before all completed 3 years of treatment	Chronic pain (OA, DPN, LBP) n = 233 39 completed 3 years	Oxycodone CR (10–293.5 mg/day) Mean dose 52.5 mg/day	+	Not reported	D/C:133/233 due to AE: 40 (17%) LOE: 18 (8%) Lost f/u: 27(12%) Other: 48 (21%)	[31]
Rauck et al. (2008)	Open label 6 months	Chronic pain (LBP, OA) n = 126	Oxymorphone (5–100, median 20 mg)	+	+ BPI	16% in titration & 17% in maintenance d/c due to AE	[39]
Wallace et al. (2009)	Open label 12 months	Chronic pain: (cancer & non-cancer) n = 388	OROS hydromorphone (32–48 mg/day)	+	Not reported	Not reported	[42]
Wild et al. (2010)	Open-label comparison study Up to 1 year	Chronic pain (LBP, OA) n = 1117	Tapentadol ER 100–250 mg b.i.d. versus oxycodone CR 20–50 mg b.i.d.	+ around 40% pain relief with both opioids	Not reported	Tapentadol gp : 22.1% Oxycodone gp: 36.8% due to AE	[41]
Friedmann et al. (2011)	Open-label, Phase III trial 12 months	Chronic pain (OA, LBP) n = 823	Remoxy (ER oxycodone) 5–80 mg b.i.d.; mean (SD) dose 32.1 (24.7) mg b.i.d.	+	Not reported	D/C: 443 (50%), due to AE 173 (21%)	[60]
Richarz et al. (2013)	Open-label comparison study 52 weeks	Chronic non-cancer pain n = 112	Hydromorphone ER versus oxycodone CR	+	Not reported	Hydromorphone 1.6% versus oxycodone 0.4%	[43]

AE: Adverse effect; b.i.d.: Twice daily; D/C: Discontinue; DPN: Diabetic polyneuropathy; LBP: Lower back pain; LOE: Loss of effect; OA: Osteoarthritis; RCT: Randomized controlled trial; SD: Standard deviation.

Table 3. Systematic reviews of opioid efficacy trials.
Study (year)	Pain condition/study type & #/n (# subjects)	Drug & route	Pain relief	Function, QOL	AE	D/C due to inadequate relief (A) or AE (B)	Opioid addiction	Conclusions	Ref.
Kalso et al. (2004)	CNCP (NeuP, NoP, mixed) RCT (15): 11/15 (on oral opioids) Open label (6/11) n = 1025 subjects (11/15 RCT)	Oral opioids (oxycodone, morphine, methadone) versus placebo Daily dose: oxycodone (20–45 mg), morphine (30–120 mg), methadone (15 mg) Route: oral & IV Study duration: 4 days to 8 weeks (RCT); 6–24 months (open label)	At least 30% mean decrease in pain in NoP & NeuP	3 out of 8 studies reported improvement. Mood & sleep improved with pain relief. No significant improvement in depression	At least 1 AE in 80% patients: constipation (41%), nausea (32%), somnolence (29%)	54% D/C 44% of 388 (open label) still on opioids at 7–24 months	Assessment limited by short f/u and small number of selected patients	Long-term efficacy indeterminate due to lack of sufficient data Concealment of blinding was questionable	[61]
Sandoval et al. (2005)	CNCP (NeuP, LBP, failed opioid Rx; no diagnosis in 50%) RCT (1), case reports (13), Case series (7) n = 545 subjects	Methadone (previous opioid therapy was not tolerated or not effective) Starting dose 0.2–80 mg/day Max dose: 20 –930 mg/day Oral	Meaningful pain relief in 59% in uncontrolled studies; Statistically significant pain relief in RCT at 20 mg/day	Not reported	Minor side effects	Not reported	Not reported	Lack of high quality studies. Response rates based on poor quality uncontrolled studies Great variability in dose	[144]
Eisenberg et al. (2006)	NeuP (peripheral or central) RCT (23): ST =14 IT = 9	Any opioid (ST: morphine, fentanyl, alfentanyl, meperidine, codeine; LT: morphine, oxycodone, methadone, Levorphanol) Any route Study duration: ST: <24 h IT: median 28 (8–70) days	ST: mixed results IT: opioids versus placebo mean decrease 13 points (0–100 VAS) in spontaneous pain equal to 30% relief	Not reported	Nausea (33%) Constipation (33%) Drowsiness (29%) Dizziness (21%) Vomiting (15%) Calculated NNH	B: 11% (opioids) versus 4% (placebo)	Not reported	No evidence on long-term efficacy	[50]
Furlan et al. (2006)	CNCP NoP 80% NeuP 12% FMS 7% Mixed 1% RCT (41) n = 6019 subjects	Any opioid: Weak (codeine, tramadol, propoxyphene) Strong (morphine, oxycodone) Oral route Study duration average 5 (1–16) weeks	Meta-analysis Opioid versus 1. placebo (n = 28) SMD -0.60, 95% CI: -0.69 to -0.50 2. Other drugs (n = 8) SMD -0.05, 95% CI: -0.32 to -0.21	Meta-analysis Opioid versus 1. Placebo (n = 20) SMD -0.31, 95% CI: -0.41 to -0.22 2. Other drugs (n = 8) SMD 0.16, 95% CI: 0.03–0.30	Compared with placebo: Constipation, nausea, dizziness, somnolence, itching Compared with other drugs: nausea, constipation, somnolence	A: 15% in opioid gp versus 30% in placebo gp. B: 21% in opioid gp versus 10% in placebo gp Overall average dropout rates 33% (opioids) versus 38% (placebo)	Drug craving in 8.7% (morphine) versus 4.3% (placebo) in 1 study	Only strong opioids were statistically superior to naproxen & nortriptyline for pain relief No differences in functional outcomes for 3 drug classes	[63]
Martell et al. (2007)	Ch back pain Total studies (35): Prevalence (11) Efficacy (15; RCT 10, open label 5) ADRB/SUD (9) n = 1008 subjects in efficacy studies	Any opioid: codeine tramadol, dextropropoxyphene, oxymorphone ER, oxycodone CR, SR morphine, morphine (topical) TD fentanyl Compared with placebo (3) Acetaminophen (2) NSAID (1) Other opioid (6) Opioid dose: 73 mg/day (SD 89; 30–232 mg/day) Oral, topical, TD Study duration 64 days (1–16 weeks)	Studies report opioids superior to placebo or active control Meta-analysis (4 studies) no reduced pain with opioids (g, -0.199 composite SMD [95% CI:, -0.49 to 0.11]; p = 0.136)	Functional status not necessarily improved with decrease in pain	ADRB: 5–24%	Retention rates 67–99%	Current SUD 3–43%; life time SUD prevalence 36–56%	Long-term efficacy (≥16 weeks) is unclear SUD are common in LBP patients on opioids Result may be biased, 73% trials were industry sponsored	[32]
Deshpande et al. (2007)	Ch LBP RCT (n = 4)	Oral tramadol versus placebo (3 trials) or oxycodone versus naproxen (1 trial) Study duration 90 days (2 trials) 16 weeks (1 trial)	Tramadol more effective than placebo: SMD 0.71 (0.39–1.02) On reanalysis no statistical significance SMD = -0.58 (-1.42 to 0.26)	Tramadol more effective than placebo: SMD 0.17 (0.04–0.30) On reanalysis no statistical significance SMD= -0.06(-0.88 to 0.76)	Headache (RD 9%, 95% CI: 6–12%) Nausea (RD 3%; 95% CI: 0–6%)	Not reported	Not reported	Question role in LBP. On repeat analysis statistically non-significant improvements in pain and function	[47]
Cepeda et al. (2007)	OA RCT (11) n = 1939 subjects	Tramadol or tramadol/paracetamol versus placebo or active control	12% relative decrease in pain intensity in tramadol or tramadol/paracetamol group	8.5% relative improvement in joint stiffness and function on WOMAC index	1 in 5 with minor AE in tramadol or tramadol/paracetamol group	B: 1 in 8 (95% CI: 7–12) in tramadol or tramadol/paracetamol group	Not reported	Small benefits in pain and function with tramadol or tramadol/paracetamol in patients with OA	[69]
Nuesch et al. (2009)	OA ( hip, knee or both) Total studies (20): RCT (10): parallel group (9) , crossover (1) n = 2268 subjects	Weak and strong non-tramadol opioids: codeine (3 trials), TD fentanyl (1 trial), morphine (1 trial), oxycodone (4 trials), oxymorphone (2 trials) versus placebo Oral or TD routes Median daily dose 51 mg morphine equivalent (13–160 mg) Study duration 4 weeks (3 days to 3 months)	Pain relief more effective with opioids than control: SMD -0.36 (95% CI: -0.47 to -0.26) or 15% (95% CI: 11–20%) difference between opioids & placebo NNT 8 (95% CI: 7–11)	Larger improvements in opioid gp SMD -0.33, (95% CI: -0.45 to -0.12); 0.7 units difference on WOMAC or 13% (95% CI: 9–18%) improvement over placebo NNT 10 (8–15)	55% more likely to have AE. RR 1.55 (95% CI: 1.41–1.70) for any AE and 3.35 (95% CI: 0.83–13.56) for serious AE NNH 12 (95% CI: 10–16)	B: 4-times more likely to dropout or withdraw in opioid group versus placebo RR 4.05, (95% CI: 3.06–5.38) NNH for dropout 19 (95% CI: 13–29)	Not reported	Non tramadol opioid benefits (small to moderate) outweighed by AE (large increases)	[48]
Noble et al. (2010)	CNCP (OA, back pain, NeuP) Total studies (27): (RCT (1); uncontrolled trial continuations or case series (26) n = 4893 subjects	Opioids: weak and strong RCT compared two opioids Route (oral (12 trials), TD (5 trials), IT (10 trials) Study duration: at least 6 months	Clinically significant decrease Variable amount of pain relief among studies	Inconclusive	Many minor AE, for example, nausea, HA	A: Oral: 10.3% TD: 5.8% IT: 7.6% B: Oral: 22.9% (weak 11.4%; strong 34.1%) TD: 12.1% IT: 8.9%	Rare at 0.27% reported in some studies	Weak evidence for clinically significant pain relief long term; Inconclusive evidence for improved function or QOL	[46]
Papaleontiou et al. (2010)	CNCP in >60 years OA (70%), NeuP (13%), Other (17%) RCT (43) Safety & efficacy (40) Misuse or abuse (3)	Any opioid (codeine, propoxyphene, tramadol, morphine, oxycodone, hydromorphone, oxymorphone, fentanyl, methadone, buprenorphine) versus placebo/NSAID/acetaminophen/TCA/gabapentin Study duration: 4 (1.5–156) weeks. Only 5 studies (12%) were >12 weeks	ES -0.557 (p < 0.001) on meta-analysis	ES -0.432 (p < 0.001) on meta-analysis	Constipation (30%), Nausea (28%), dizziness (22%)	A: 8% (0–47%) in opioid versus 16% (0–67%) in control group B: 25% (3–52%) in opioid group versus 8% (-24%) in comparator group	Abuse and misuse behaviors negatively associated with older age (in 1 study 1% >60 and 4% <60 years)	Long-term safety, efficacy, and abuse potential not known. Short-term improvement in pain intensity and physical function but poorer mental health function	[52]
Furlan et al. (2011)	CNCP: NoP (87.1%; OA, RA, non-radicular back pain) NeuP (9.2%; DPN, PHN, phantom limb pain, regional cervico-brachial) FMS (3.2%) Mixed (0.41%) RCT (62): EERW & non-EERW trials n = 11,927 participants (7807 completed, 4120 dropped out)	9 opioids: tramadol, propoxyphene, morphine oxycodone, oxymorphone, methadone, TD fentanyl, TD buprenorphine 47 trials with placebo control 8 trials compared with NSAID Study duration: <6 weeks (46 trials) 11–16 weeks (15 trials) 24 weeks (1 trial on propoxyphene)	Medium ES in favor of opioids (ES = 0.58, 95% CI: 0.48–0.67) Only strong opioids more effective than Naproxen 1000 mg/day Weak or strong opioids not more effective than TCA or AED	Small ES (ES = 0.34, 95% CI: 0.25–0.43) NSAIDs significantly better than opioids but with very small ES (0.18) Opioids not more effective than TCA or AED	Statistically & clinically significant AE: Nausea (17%), constipation (20%), somnolence/drowsiness (14%), dizziness/vertigo (12%), dry skin/itching/pruritus (10%), vomiting (11%)	Average dropout is 35% (opioid) versus 38% (control) A: 15% (opioid group) versus 30% (control) B: 21% (opioid group) versus 10% (control) AE Underestimated in EERW trial design	Not reported	Opioids more effective than placebo: NoP (ES = 0.60, 95% CI: 0.49–0.72) and NeuP (ES = 0.56, 95% CI: 0.38–0.73) Industry funding in 47 trials & 87% with some kind of relationship	[51]
White et al. (2011)	Chronic LBP A summary of previous Cochrane reports RCT	Three drug classes versus alternative Rx for CLBP: opioids, NSAIDs, antidepressants	Opioids more effective than placebo Opioids versus NSAIDs, no greater benefit in terms of pain & disability	Opioids more effective than placebo with much greater effect size for pain than disability Opioids are no better than NSAIDs	Compared with placebo, significantly greater AE (differences of 2 and 9%)	Not reported	Not reported	Favorable effectiveness compared with placebo, but similar effectiveness compared with NSAIDs & significant side effects & decreased effect with long-term use	[53]
Whittle et al. (2011)	RA RCT: 11 n = 672 participants	Weak & strong opioids: codeine, dextropropoxyphene, tramadol, tilidine, pentazocine, morphine versus placebo or (NSAID, paracetamol/acetaminophen) Study duration: <1 week: 4 trials 1–6 weeks: 7 trials	Superior to placebo RR 1.44 (95% CI: 1.03–2.03) NNT 6 (95% CI: 3–84) NEAR RR (1.20, 95% CI: 0.89–1.61) no difference between opioids & placebo	3 trials assessed function, 1 trial reported improvement	Risk of AE higher with opioids OR 3.90 (95% CI: 2.31–6.56)	A: no different than placebo based on pooled data (4 trials). RR 0.82 (95% CI: 0.34–2.01)		No long-term evidence >6 weeks	[49]

ADRB: Aberrant drug-related behaviors; AE: Adverse effect; AED: Antiepileptic drugs; CNCP: Chronic non-cancer pain; D/C: Discontinue; DPN: Diabetic polyneuropathy; EERW: Enriched enrollment; FMS: Fibromyalgia syndrome; IT: Intermediate term; LBP: Low back pain; LOE: Loss of effect; NeuP: Neuropathic pain; NoP: Nociceptive pain; OA: Osteoarthritis; PHN: Post-herpetic neuralgia; RA: Rheumatoid arthritis; RCT: Randomized controlled trial; RR: Relative risk; SMD: Standardized mean difference; ST: Short term; SUD: Substance use disorder; TCA: Tricyclics.