Clinical Practice Guideline
Long-Term Opioid Use in Non-Cancer Pain
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Background: The long-term use of opioid analgesic drugs to treat chronic non-cancer pain (CNCP) is a major component of pain pharmacotherapy. The interpretation of the evidence concerning its efficacy and risks is currently debated.
Methods: An interdisciplinary evidence- and consensus-based S3 guideline was updated on the basis of a systematic literature search (CENTRAL, Medline, and Scopus databases, from October 2008 to October 2013); meta-analyses of randomized controlled trials (≥ 4 weeks); and a consensus procedure, as specified by the AWMF regulations, including 22 medical and psychological societies and 2 patient self-help organizations.
Results: 119 publications were used to update the guideline, and 6 systematic reviews with meta-analyses were performed. A nominal group process was used to formulate recommendations concerning the indications and contraindications for the treatment of CNCP with opioid analgesics and the manner in which such treatments should be carried out. Opioid analgesics are an option for the short-term treatment (4–12 weeks) of chronic pain due to osteoarthritis (pain intensity, standardized mean difference [SMD]: –0.22 and –0.26), diabetic polyneuropathy (SMD –0.74), post-herpetic neuralgia (SMD –0.58), and chronic low back pain (SMD: –0.29 and –0.74). Long-term opioid treatment (≥ 26 weeks) for these diseases benefits only about 25% of patients. For other conditions, either short- or long-term treatment with opioid analgesics should be considered an individual therapeutic trial. Opioid treatment for pain is contraindicated by primary headaches and by any functional or mental disorder of which pain is a leading manifestation.
Conclusion: To minimize the risks of opioid analgesic treatment, physicians must be aware of its contraindications and must regularly reassess its efficacy and side effects. Pharmacotherapy should be combined with other types of treatment.
In a representative survey of persons in Germany aged 14 and older, carried out in 2013, 7.4% of respondents met the criteria for disabling chronic non-cancer pain (CNCP) (1). CNCP is associated with high costs, both direct and indirect (2). In Germany, opioid analgesics are often used to treat CNCP over the long term (i.e., for 3 months or longer) (e1).
Routine data from German health insurance carriers have revealed an increase in recent years in the short- and long-term prescribing of opioid analgesics to treat CNCP. The number of prescriptions of weak and strong opioid analgesics for longer than three months among BEK insurees who had non-malignant diagnoses rose from 1.9% in 2006 to 2.1% in 2009 (3). In 2000, 5.3% of the insurees of the AOK and KV Hesse insurance carriers who did not have cancer received at least one prescription for an opioid analgesic; in 2010, the comparable figure was 6.9%. Among insurees receiving at least one prescription for an opioid analgesic, the percentage under long-term opioid treatment (>90 days) was 4.3% in 2001 and 7.5% in 2009 (4).
The long-term use of opioid analgesics to treat CNCP is controversial in Germany, as in other countries, because of the discrepancy between clinical practice and the extant evidence base (5–7, e1, e2). Critical attitudes are sometimes said to reflect an “opioid phobia” that can harm both patients and their physicians (e3–e5). On the other hand, recent review articles and editorials from the United States have highlighted a marked rise in opioid prescriptions and in opioid-related deaths, referring to a so-called “opioid epidemic.” The long-term efficacy and safety of opioid analgesics are now being called in question (6, 7, e1).
The guideline takes positions on the indications and contraindications for opioid analgesic treatment for 4 weeks or more and the manner in which such treatment should be carried out, based on detailed analysis of the evidence and structured consensus formation. For the basic question of the utility of opioid analgesics in the treatment of chronic pain syndromes, compared to non-opioid drugs and other treatments, the reader is referred to the German S3 guidelines for the treatment of the respective conditions.
Updating of the guideline
The first version of this guideline was prepared according to the then-current methodological standards for S3 guidelines and published in 2008 (5). The large amount of new scientific evidence that has emerged since then has made it necessary for this guideline to be updated.
The directors of the German Pain Society named 17 persons (clinicians, experts on guideline preparation, patient representatives) to the steering committee for the creation of the updated guideline, on the basis of their clinical and/or scientific expertise. These persons included practitioners of primary care medicine, anesthesiology, internal medicine (with geriatrics), neurology, orthopedics/trauma surgery, psychosomatic medicine, palliative-care medicine, and clinical psychology (eBox 1).
All societies representing a medical specialty in which physicians caring for adult patients must undergo continuing medical education were invited to participate in the consensus group. The following were also invited:
- specialty societies that had participated in the creation of the original version of the guideline,
- the German Society for Pain Medicine (Deutsche Gesellschaft für Schmerzmedizin),
- three patient self-help organizations (eTable 1).
Die German Dermatological Society (Deutsche Dermatologische Gesellschaft), the German Society for Pain Medicine, and the German Pain League (Deutsche Schmerzliga) declined to participate.
The conflicts of interest declared by the members of the guideline group are documented in the guideline’s Methods section. They were evaluated by two directors of the German Pain Society (a psychologist and a physician) who did not participate in the creation of the guideline, with the aid of a representative of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF).
The search strategy was developed on the basis of current Cochrane reviews regarding the use of opioid analgesics in the treatment of CNCP (8, 9) and the protocol of a systematic review of pertinent randomized controlled trials (RCTs) (10). For the creation of the guideline, a search was carried out for randomized trials of at least 4 weeks’ duration in which opioid analgesics were compared with placebo and/or other analgesics for the treatment of CNCP. Open-label extension studies of RCTs and cohort studies were also assessed for the information they contained regarding long-term efficacy and risks. The search was performed in the CENTRAL, Medline, and Scopus databases for the period October 2008 to October 2013.
The guideline creation process also made use of a systematic review (12) of earlier guidelines (published up to July 2013) on the treatment of CNCP with opioid analgesics, which were assessed with the AGREE instrument (Appraisal of Guidelines for Research and Evaluation) (11). A total of 119 publications were used in the creation of the updated guideline (Figure).
Meta-analyses on the following topics were carried out by teams consisting of members of the steering committee along with other, external team members:
- placebo-controlled trials of opioid analgesics for osteoarthritis pain (13), neuropathic pain (14), and low back pain (15);
- direct comparisons of opioid analgesics with other analgesics for the treatment of CNCP (16);
- direct comparisons of different types of opioid analgesics for the treatment of CNCP (17);
- open-label extension studies of at least 26 weeks’ duration, in the aftermath of RCTs of at least 2 weeks’ duration for the treatment of CNCP (18).
The following variables were quantitatively evaluated:
- Efficacy: pain intensity, percentage of patients obtaining at least 50% pain relief, global improvement (percentage of patients who reported to be much or very much improved), subjective physical impairment.
- Tolerability: the percentage of patients who dropped out of the trial because of adverse effects.
- Safety: the percentage of patients with severe adverse effects, and the percentage of patients who died.
Quantitative data analysis was performed with the Revman software package (e6). The effect measures were the absolute risk differences for dichotomous variables and standardized mean differences (SMD) for continuous variables, which were calculated with a random-effect model (method of inverse variance).
Uncertainty was expressed in the form of 95% confidence intervals (CI). For dichotomous variables, the threshold value for a relative benefit or relative harm was set at a 10% decrease or increase of relative risk (8). Effect strengths expressed as standardized mean differences were classified in the scheme of Cohen:
- 0–0.2: not substantial
- 0.2–0.5: weak
- 0.5–0.8: moderate
- >0.8: strong (e7).
The minimal important difference was set at SMD ≥ 0.2 (e8). Software tools of the Cochrane Musculoskeletal Group were used to calculate the number needed to benefit (NNTB) and number needed to harm (NNTH) for dichotomous variables, and to convert SMD values into NNTB and NNTH values. For SMD-to-NNT (number needed to treat) conversions, the minimal clinically important difference (MCID) between opioid analgesics and placebo was set at 15%. The methodological quality of published studies was assessed with the GRADE scheme (Grading of Recommendations Assessment, Development and Evaluation) (e9).
The key questions and recommendations of the guideline were developed by the steering committee in 14 Delphi rounds. The consensus group then voted on the recommendations over the Internet from 22 May to 11 June 2014. The consensus group held a final consensus conference, moderated by a representative of the AWMF, on 4 July 2014. The wider public was given the opportunity to comment on the guideline from 15 July to 31 August 2014; in response to these comments, a few of the recommendations and/or the accompanying explanations were modified in a further four Delphi rounds by the steering committee and the consensus group.
The recommendation strengths were formulated as specified in the AWMF regulations (19). The evidence levels (according to the Oxford scheme) (e10) were of prime importance for the derivation of recommendation grades: the higher the evidence level, the stronger the recommendation. In general, a grade A (strong) recommendation was issued on the basis of grade 1 evidence, a grade B recommendation on the basis of grade 2 evidence, and a discretionary recommendation on the basis of evidence of grade 3, 4, or 5 (e11).
Aside from the level of evidence, the assignment of recommendation grades also took the following aspects into account: physicians’ ethical responsibilities, the clinical relevance of the efficacy measures used in the trials, the applicability of the trial findings to the target group of patients, patients’ wishes, and the practicality of implementation. A consideration of any of these aspects could result in a recommendation becoming stronger or weaker than it would have been on the basis of the evidence grade alone (19). To make such changes transparent, the steering committee used a Delphi procedure to determine a priori what criteria would be considered permissible for strengthening or weakening the recommendations (e11). The clinical consensus point (CCP), a further category of recommendation, was adopted as used in the German National Disease Management Guidelines: a recommendation of this type indicates a consensus in the guideline-creating group that the intervention in question is good clinical practice, i.e., a standard of care for which no scientific or experimental justification is possible or desired (e12). The recommendations do not explicitly take any considerations of health economics into account. The final guideline conference also determined the strength of each consensus that was reached (e13).
The guideline was externally assessed by the Drug Commission of the German Medical Association and by the Swiss and Austrian Pain Societies.
Guideline contents and recommendations concerning the administration of opioid analgesics to treat CNCP
Short-term efficacy and risks (trial duration: 4–16 weeks)
Two or more RCTs on the treatment of specific types of pain with opioids are available only for chronic osteoarthritis, chronic low back pain, diabetic polyneuropathy, and post-herpetic neuralgia. For patients with these conditions, it has been shown that opioid analgesics relieve pain and subjective physical impairment better than placebo. Opioids are as safe as placebo, but less well tolerated (Table 1 and eTable 2).
Long-term efficacy and risks (trial duration: 26–108 weeks)
In a randomized trial of 6 months’ duration involving 199 patients with chronic pain due to osteoarthritis, transdermal buprenorphine was not found to be significantly better than placebo for the reduction of pain or subjective physical impairment (p = 0.06 for both) (e14).
In an open, controlled trial, 675 patients with chronic low back pain (nociceptive, neuropathic, or mixed) were treated with either transdermal fentanyl or oral morphine for 13 months. 37% of the patients in the fentanyl group and 37% in the morphine group stated, at the end of the treatment, that their pain at rest had improved by at least 50%; for pain during movement, the corresponding figures were 40% and 50%, respectively. Average physical functional ability improved significantly (p<0.0001), from 29 to 37 on a 0–100 scale, in both groups. The rate of premature termination of treatment was 37% in the fentanyl group and 31% in the morphine group. Deaths or behavior typical of addiction were not observed (e15).
In an open, controlled trial of 52 weeks’ duration, 1117 patients with chronic low back pain or osteoarthritis pain were treated with either tapentadol or oxycodone. The mean (with standard error) of pain intensity declined, from the beginning to the end of the trial, from 7.6 (0.05) to 4.4 (0.09) in the tapentadol group and from 7.6 (0.11) to 4.5 (0.17) in the oxycodone group. 48.1% (394/819) of the patients in the tapentadol group and 41.2% (73/177) of those in the oxycodone group reported to be much or very much improved. The rate of termination of treatment because of adverse effects was 23% for tapentadol and 37% for oxycodone. Deaths or behavior typical of addiction were not observed (e16).
Eleven open-label extension studies of placebo-controlled RCTs with a total of 2445 subjects with nociceptive pain (back pain, osteoarthritis pain) and neuropathic pain (radiculopathy, polyneuropathy) were included in the meta-analysis. The median study duration was 26 weeks (range, 26 to 108 weeks). There were four studies of oxycodone, two of tramadol, and one each of buprenorphine, hydromorphone, morphine, oxymorphone, and tapentadol. 28.5% of the initially randomized patients completed the open-label phase; 4.9% terminated it prematurely because of inadequate pain relief, and 16.8% did so because of adverse effects. 0.08% of the patients died during the open-label phase. Only a single study, from the United States, systematically investigated opioid abuse: 5.7% of the patients met the criteria for opioid abuse as assessed by the study directors, and 2.6% did so as assessed by independent experts (18).
Risks of opioid analgesics in cohort studies
In a systematic review of 67 studies, mainly from the USA, the prevalence of abuse of prescribed opioids ranged from 0.2% to 3.3% (20). Case series from German pain centers revealed no evidence of problematic drug-taking behavior among highly selected patients (21, 22). A panel of experts convened by the German federal government examined this question with the aid of data from various sources (inquiries to pharmacists and addiction clinics, analyses of routine data from health-insurance carriers, information from the Federal Chamber of Pharmacists and the Federal Criminal Police Office) and found no evidence of any numerically significant degree of abuse of tilidine or tramadol (23).
Cohort studies from the USA have shown higher mortality among elderly persons treated with opioids for painful osteoarthritis and rheumatoid arthritis than among those treated with non-steroidal anti-inflammatory drugs (24). The following have been discussed as potential reasons for this finding: inadvertent overdose, self-medication, worsening of sleep apnea, and fractures due to falls (24, 25).
Potential indications for short-term treatment (4–12 weeks)
Quantitatively and qualitatively adequate evidence for treatment with opioid analgesics for 4 to 12 weeks exists for chronic pain due to osteoarthritis, diabetic polyneuropathy, and post-herpetic neuralgia, and for chronic low back pain. Short-term opioid analgesic treatment for other indications should be viewed as an individual therapeutic trial (Table 2).
Potential indications for long-term treatment (>26 weeks)
Quantitatively adequate evidence exists for chronic pain due to osteoarthritis, diabetic polyneuropathy, and post-herpetic neuralgia, and for chronic low back pain. The percentage of patients whose symptoms improved spontaneously cannot be determined from the studies that were analyzed, as they lacked control groups; nor can it be determined how many patients additionally received uncontrolled accompanying treatments. Long-term opioid analgesic treatment for other indications should be viewed as an individual therapeutic trial.
Contraindications for treatment
Contraindications for treatment with opioid analgesics are listed in Table 3.
Treatment with opioid analgesics in practice
The manner of treatment with opioid analgesics in clinical practice is explained in Boxes 1 and 2.
The drug to be used should be chosen in consideration of the type of chronic pain syndrome from which the patient is suffering, any accompanying medical conditions, any contraindications, the patient’s preferences, the good and bad effects of previous treatments, and the risk–benefit profile of alternative drugs and non-pharmacological treatments.
Patients with CNCP should not be given opioid analgesics as their sole treatment for this condition. Self-help resources and physical, physiotherapeutic, and/or psychotherapeutic techniques (including patient education) and/or lifestyle modification, should be used as complements to drug treatment for pain.
Emotional and functional disturbances of which pain is a major manifestation are contraindications to opioid treatment. Therefore, psychosocial screening is recommended; if evidence is found that the symptoms have a relevant psychosocial component, then the patient should be interviewed by a psychotherapist. The treating physician should be sure to inform the patient, before an opioid is taken, of the effects of the drug on driving ability, possible impaired performance and risks in the workplace, and any individually relevant risks, e.g., falls and confusion in the elderly or loss of libido in younger patients. Unjustified fears or unrealistic expectations should be addressed and corrected before opioid treatment is begun. The dose should start low and rise slowly; the patient should be told that adverse effects such as nausea and light-headedness, if they arise, may resolve spontaneously in 2–4 weeks even without any dose reduction. Opioid-induced constipation should be treated with adequate doses of laxatives (possibly prophylactically). A morphine equivalent dose above 120 mg per day is inadvisable.
The indications for terminating treatment with opioid analgesics are listed in eBox 2.
For patients with persistently severe pain and/or physical impairment despite the long-term use of opioids, opioid withdrawal can be considered as a therapeutic intervention within the framework of a multimodal treatment program. Recommendations for the treatment of special types of patients (the elderly, children, adolescents, pregnant women, and persons with mental disturbances, including substance abuse) are given in eBox 3.
Opioid analgesics are an important option for the drug treatment of chronic osteoarthritis pain, low back pain and neuropathic pain. Some, but not all, patients treated with opioid analgesics experience long-term relief (for at least 26 weeks) of pain and subjective physical impairment, without any major adverse effects. Opioid analgesics have significant risks (drug abuse, sexual dysfunction, elevated mortality); to minimize them, physicians must be aware of the contraindications and they must regularly reassess the efficacy and adverse effects of treatment. Pharmacotherapy should be combined with physical and physiotherapeutic measures and pain psychotherapy if indicated. Clearly, the short- and long-term opioid treatment of CNCP should not be expanded incautiously and unthinkingly; yet it must not be categorically rejected, either. A central aim of further research will be to assess the long-term efficacy and risks of opioid analgesics on the basis of pain registry data and routine data from health-insurance carriers.
Conflict of interest statement
PD Dr. Häuser owns mutual stock funds that may contain pharmaceutical company stock. He has been paid for serving on an advisory board for Daiichi Sankyo. He has received lecture honoraria from the Abbott, Janssen-Cilag, MSD, Sharp & Dohme, and Pfizer companies.
Dr. Bock has received reimbursement of meeting participation fees from the Mundipharma and Grünenthal companies. He has received reimbursement of travel expenses and lecture honoraria from Mundipharma.
Prof. Petzke has served as a paid consultant for the Grünenthal, Epionics Spine, and Janssen-Cilag companies. He has received research support (third-party funding) and reimbursement of travel expenses from Janssen-Cilag.
Prof. Tölle has been paid for serving on advisory boards for Mundipharma, Janssen-Cilag, Grünenthal, and Ratiopharm. He has received support for travel expenses from Mundipharma and research support (third-party funding) from Pfizer.
Dr. Engeser and Dipl.-psych. Willweber-Strumpf state that they have no conflict of interest.
Manuscript submitted on 14 July 2014, revised version accepted on 31 July 2014.
Translated from the original German by Ethan Taub, M.D.
PD Dr. med. Winfried Häuser
Klinik Innere Medizin
66119 Saarbrücken, Germany
@For eReferences please refer to:
eBoxes and eTables:
s00482–014–1432–4; epub ahead of print (last accessed on 2 September 2014).
Orthopedic Center am grünen Turm, Grüner-Turm-Straße 4–10, Ravensburg: Dr. med. Bock
Primary care practice, Hohenzollernstraße 36, Pforzheim and Department of General Practice and Health Services Research at Heidelberg University, Heidelberg: Dr. med. Engeser
Department of Neurology, Technische Universität München, Munich: Prof. Dr. med. Dr. rer. nat. Tölle
Pain Day Hospital and Outpatient Clinic, University of Goettingen, Göttingen: Dipl.-Psych. Willweber-Strumpf, Prof. Dr. med. Petzke
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