Long‐term opioid management for chronic noncancer pain Edited (no change to conclusions), comment added to review



Opioid therapy for chronic noncancer pain (CNCP) is controversial due to concerns regarding long‐term effectiveness and safety, particularly the risk of tolerance, dependence, or abuse.


To assess safety, efficacy, and effectiveness of opioids taken long‐term for CNCP.

Search methods

We searched 10 bibliographic databases up to May 2009.

Selection criteria

We searched for studies that: collected efficacy data on participants after at least 6 months of treatment; were full‐text articles; did not include redundant data; were prospective; enrolled at least 10 participants; reported data of participants who had CNCP. Randomized controlled trials (RCTs) and pre‐post case‐series studies were included.

Data collection and analysis

Two review authors independently extracted safety and effectiveness data and settled discrepancies by consensus. We used random‐effects meta‐analysis' to summarize data where appropriate, used the I2 statistic to quantify heterogeneity, and, where appropriate, explored heterogeneity using meta‐regression. Several sensitivity analyses were performed to test the robustness of the results.

Main results

We reviewed 26 studies with 27 treatment groups that enrolled a total of 4893 participants. Twenty five of the studies were case series or uncontrolled long‐term trial continuations, the other was an RCT comparing two opioids. Opioids were administered orally (number of study treatments groups [abbreviated as "k"] = 12, n = 3040), transdermally (k = 5, n = 1628), or intrathecally (k = 10, n = 231). Many participants discontinued due to adverse effects (oral: 22.9% [95% confidence interval (CI): 15.3% to 32.8%]; transdermal: 12.1% [95% CI: 4.9% to 27.0%]; intrathecal: 8.9% [95% CI: 4.0% to 26.1%]); or insufficient pain relief (oral: 10.3% [95% CI: 7.6% to 13.9%]; intrathecal: 7.6% [95% CI: 3.7% to 14.8%]; transdermal: 5.8% [95% CI: 4.2% to 7.9%]). Signs of opioid addiction were reported in 0.27% of participants in the studies that reported that outcome. All three modes of administration were associated with clinically significant reductions in pain, but the amount of pain relief varied among studies. Findings regarding quality of life and functional status were inconclusive due to an insufficient quantity of evidence for oral administration studies and inconclusive statistical findings for transdermal and intrathecal administration studies.

Authors' conclusions

Many patients discontinue long‐term opioid therapy (especially oral opioids) due to adverse events or insufficient pain relief; however, weak evidence suggests that patients who are able to continue opioids long‐term experience clinically significant pain relief. Whether quality of life or functioning improves is inconclusive. Many minor adverse events (like nausea and headache) occurred, but serious adverse events, including iatrogenic opioid addiction, were rare.


Meredith Noble, Jonathan R Treadwell, Stephen J Tregear, Vivian H Coates, Philip J Wiffen, Clarisse Akafomo, Karen M Schoelles, Roger Chou


Plain language summary

 Opioids for long‐term treatment of noncancer pain 

The findings of this systematic review suggest that proper management of a type of strong painkiller (opioids) in well‐selected patients with no history of substance addiction or abuse can lead to long‐term pain relief for some patients with a very small (though not zero) risk of developing addiction, abuse, or other serious side effects. However, the evidence supporting these conclusions is weak, and longer‐term studies are needed to identify the patients who are most likely to benefit from treatment.


Meredith Noble, Jonathan R Treadwell, Stephen J Tregear, Vivian H Coates, Philip J Wiffen, Clarisse Akafomo, Karen M Schoelles, Roger Chou

Reviewer's Conclusions

Authors' conclusions

Implications for practice

Most of the participants in these studies had back pain, often following failed back surgery, osteoarthritis, or neuropathic pain. These findings should not be generalized to patients with chronic pain of other types, such as headache. Concern that an individual with CNCP may develop dependence on the drug during long‐term administration represents a potential barrier to treatment. However, the rate of observed signs of opioid addiction was extremely low in the body of evidence considered in this review (0.27%, conservatively). This rate would be 0.14% if no addictive behaviors occurred among the studies that did not mention addiction rates at all. Only three participants were reported as having potential abuse problems. These numbers do not support the contention that potential iatrogenic opioid addiction should limit therapy for well‐selected and well‐supervised patients. Because most studies screened out potential participants with histories of substance abuse or addiction, the rates of addiction reported in these studies are only generalizable to patients without a history of addictive/abusive behaviors. This finding is consistent with that of another review article on opioid abuse and addiction that calculated an abuse/addiction rate of 0.19% in studies that prescreened chronic pain patients for long‐term opioid use or addiction/abuse history, and 3.27% in all studies (Fishbain 2008). Given the complexity of definitively diagnosing opioid addiction (see Ballantyne 2006) and in the interest of capturing the overall effect of opioid therapy on quality of life, we sought to analyze health‐related quality‐of‐life outcomes in this review. However, findings on quality of life were inconclusive for all modes of administration.

Implications for research

The Mayday Fund (www.maydayfund.org), a foundation sponsoring pain treatment research, asked ECRI Institute to review issues including the efficacy and safety of opioids for noncancer pain in 2004. The Milbank Memorial Fund (www.milbank.org) invited an international group of pain researchers to help formulate key questions. Representatives from these organizations and additional pain researchers critiqued the review and made recommendations for future research. Allowing rescue opioids (with the amount and frequency of dosage as an outcome) in placebo or nonopioid groups may circumvent ethical problems of withholding treatment from individuals with CNCP in long‐term RCTs. Protocols should specify uniform diagnostic and data collection criteria (e.g., pain etiology, drugs prescribed, dosing regimens) and mimic clinical practice (e.g., drug combinations could be used, drug changes could be made, drug dosage could be titrated slowly and adjusted, adverse effects could be aggressively managed). Reasons for discontinuation, including satisfied departures, must be documented. Long‐term poorly‐understood effects, including androgen deficiency and changes in immune function, must be documented. However, practical/pragmatic RCTs might be cost prohibitive (Tunis 2003). Adequately powered, well‐designed prospective cohort studies could provide useful information (Geborek 2002; MacDonald 2003; Mamdani 2002). Long‐term dose‐dependent efficacy and adverse effects could be researched in existing databases (e.g., European Medicines Evaluation Agency, FDA, Australia Therapeutic Goods Administration). Studies on U.S. Veterans Healthcare Administration data are examples of retrospective analyses (Hermos 2004; Mahowald 2005; Reid 2002; Ytterberg 1998).

Despite the identification of 26 treatment groups with 4768 participants, the evidence regarding the effectiveness of long‐term opioid therapy in CNCP is too sparse to draw firm conclusions, including quantity of mean of pain relief. Poor reporting reduced the amount of acceptable data. Studies should always report data needed for meta‐analysis (mean, standard deviation, number of participants, or data to calculate them), and authors of studies for which these data were not originally published should consider making them publicly available. Studies should also use validated scales, report intention‐to‐treat data in addition to completer analyses, and conduct post‐hoc analyses to identify prognostic factors for treatment success.

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