The opioid epidemic and the long-term opioid therapy ...

Pain Management

Perspective For reprint orders, please contact: [email protected]

The opioid epidemic and the long-term opioid therapy for chronic noncancer pain revisited: a transatlantic perspective Winfried Häuser*,1,2, Frank Petzke3, Lukas Radbruch4 & Thomas R Tölle5

Practice points ●●

T he pro and con discussion on the benefits and harms of long-term opioid therapy (LtOT) for chronic noncancer pain (CNCP) divides the pain community in North America and Europe.

The opioid epidemic ●●

T he opioid epidemic (marked rise of opioid prescriptions and associated misuse, abuse and deaths) in the last 10 years is a North American, but not a European phenomenon. Physician-, patient- and society-related reasons for the opioid epidemic in North America have been considered.

Appraisal of the evidence of efficacy of LtOT for chronic noncancer pain ●●

ecent US and German systematic reviews differ in their appraisal of the evidence of the long-term efficacy and R safety of LtOT for CNCP, with a more positive view in Europe and a negative one in the USA.

Good clinical practice: guidelines recommendations ●●

ecent North American and European guidelines gave similar recommendations for a good clinical practice of LtOT R for CNCP. LtOT should only be performed in patients which responded to an opioid trial (opioid responders). Drug holidays should be regularly discussed with opioid responders.

Defining indications & contraindications for LtOT of noncancer pain: untying chronic noncancer pain ●●

hronic pain as the main symptom of functional disorders (e.g., fibromyalvgia, irritable bowel syndrome) and of C mental disorders (e.g., somatoform pain disorder) should not be treated with opioids.

Opioids in CNCP syndromes: first line, second line, third line, never? ●●

T he selection of pharmacotherapy should consider the chronic pain syndrome in question, the patient’s comorbidities, contraindications, the patient’s preferences, benefits and harmful effects of previous treatments, as well as the risk–benefit profiles of drug-based and nondrug-based treatment alternatives.

Conclusion ●●

pioid analgesics remain an important option for the drug treatment of carefully selected patients with chronic O osteoarthritis pain, low back pain and neuropathic pain.

Future perspective ●●

etter education of the prescribing physicians to consider contraindications of LtOT and the avoidance of high-dose B opioid therapy and access to psychosocial services for patients might reduce the opioid epidemic in North America.

Internal Medicine 1, Klinikum Saarbrücken, Winterberg 1, D-66119 Saarbrücken, Germany Department of Psychosomatic Medicine & Psychotherapy, Technische Universität München, Ismaningerstraβe 22, D-81675 München, Germany 3 Day Clinic & Out Patient Department Pain Therapy, Universitätsmedizin Göttingen, D-37075 Göttingen, Germany 4 Department of Palliative Medicine, University Hospital Bonn, Center of Palliative Care, Malteser Hospital Seliger Gerhard Bonn/Rhein-Sieg, D-53127 Bonn, Germany 5 Department of Neurology, Technische Universität München, Ismaningerstraβe 22, D-81675 München, Germany *Author for correspondence: Tel.: +49 681 9632020; Fax: +49 681 9632022; [email protected] 1 2

10.2217/pmt.16.5 © 2016 Future Medicine Ltd

Pain Manag. (Epub ahead of print)

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ISSN 1758-1869

Perspective Häuser, Petzke, Radbruch & Tölle Keywords

• chronic noncancer pain • guidelines • long-term opioid therapy • misuse and addiction • mortality • opioids • opioid abuse • systematic review

The rise of opioid prescriptions and associated deaths (‘opioid epidemic’) in North America has evoked worldwide discussions on the long-term efficacy and safety of long-term opioid therapy (LtOT) for chronic noncancer pain (CNCP). We discuss if the opioid epidemic is a real worldwide or a more North American phenomenon. We consider reasons of the opioid epidemic. We highlight differences in the appraisal of the evidence of recent systematic reviews on LtOT for CNCP of US and European authors. We discuss similarities and differences of recent North American and European guidelines on LtOT for chronic CNCP. We point out potential indications and contraindications of LtOT in CNCP syndromes. First draft submitted: 17 April 2015; Accepted for publication: 2 February 2016; Published online: 18 March 2016 Chronic pain has been defined as pain lasting longer than 3 months or past the normal time for tissue healing [1] . The armamentarium of treatment for chronic noncancer pain (CNCP) and cancer-related pain includes a variety of drugs and/or physical therapies and/or psychological therapies and/or procedure interventions. Opioids are believed to be a mainstay for the treatment of cancer-related pain, but may also have value as one treatment option of drug therapy of CNCP. Long-term opioid therapy (LtOT) has been defined by daily or near-daily use of opioids for at least 90 days, but in practice, they are often used indefinitely [2] . The long-term use of opioid analgesics to treat CNCP is a matter of debate in North America and Europe driven by a historic perspective of undertreatment of chronic pain. Review articles and editorials from the USA have highlighted a marked rise in opioid prescriptions with a parallel increase in opioid abuse/misuse and deaths (‘a flood of opiods and a rising tide of deaths’ [3] , a so-called ‘opioid epidemic’ [4] . Some authors claimed a ‘worldwide opioid epidemic’ [5] . In parallel to the discussion on the opioid epidemic, the long-term efficacy and safety of opioid analgesics for CNCP were put into question [5 - 6,7] . In this context, some clinicians in the USA and Europe worried that the pendulum in the ‘war’ on opioids in CNCP has swung too far, and as a consequence, this has not benefited neither patients with pain nor society as a whole [8] . However, some fear that the ‘war’ against illicit drugs and a ‘restrictive’ approach to opioid prescription for chronic pain may not at all decrease illicit drug use and diversion but could, instead, lead to inadequate treatment of chronic pain, because of irrational restrictions of their medical use [9] . Critical attitudes toward LtoT prescription for CNCP have been labeled an ‘opioid phobia’ that can harm both patients and their physicians [10] .

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Facing the discussion on LtOT für CNCP, the aim of this narrative review is to point out some similarities and differences between North America and Europe regarding: ●● The perception of an existing opioid epidemic; ●● The appraisal of the evidence on the long-term

efficacy and harms of opioids by systematic reviews; ●● The recommendations of recent evidence- and

consensus-based guidelines on LtOT therapy for clinical practice in CNCP. The paper is based on a selective search of the literature. For the topic of the opioid epidemic, we present recent data on opioid use for CNCP in North America and Europe based on a themerelated selection of relevant information in the literature. For the topic of the evidence on the benefits and harms of LtOT in CNCP, we compare the appraisal of evidence of the report/technology assessment on the Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain by the Pacific Northwest Evidence-based Practice Center [7] with the the recent update of the German guidelines on long-term opioid therapy in CNCP (LONTS) [11–17] . The US evidence report was based on a systematic search of the literature (MEDLINE, CRENTRAL,PsycINFO and CINAHL to August 2014) [7] . LONTS update was an interdisciplinary evidence- and consensus-based guideline based on a systematic literature search (CENTRAL [Cochrane Central Register of Controlled] Trials, MEDLINE, and Scopus databases, up to October 2013); metaanalyses of randomized controlled trials with opioids (≥4 weeks) and a consensus procedure, as specified by the Association of the Medical Scientific Societies in Germany (AWMF) regulations, including 22 medical and psychological societies and two patient self-help organizations [11] . For the topic of clinical practice

future science group

The opioid epidemic & the long-term opioid therapy for chronic noncancer pain revisited guidelines, we compare the recommendations of LONTS Update [11] with the ones of the American Pain Society and American Academy of Pain Medicine [18] and of the Canadian guidelines for safe and effective use of opioids for CNCP [19] . The opioid epidemic

Perspective

of opioid prescriptions differed substantially between countries. However, these data do not reveal for which clinical situation opioids were prescribed: Time-limited pain management of medical procedures, acute injury and disease, palliative care of patients with late-stage or end-stage disease or short-term or long-term ma nagement of CNCP.

●●Prevalence of chronic pain

The prevalence rates of CNCP in the general population range between 20 and 30% in North America and European surveys [20–22] . The wide range of prevalence rates can be partially explained by the different wordings and time frames for chronic pain used in the various surveys [20] . Up to ten-times more participants of these surveys reported CNCP than chronic cancer related pain. Opioid prescriptions ●●Global consumption of opioids

Global consumption of strong opioids (in morphine equivalent units) increased more than 30-fold from 1980 to 2010 [23] . International statistics show an overwhelming concentration of opioid usage concentrated in very few industrialized countries in the world. A report from the United Nations showed that 90% of the global consumption of morphine, fentanyl and oxycodone registered in occurred in the USA, Canada, Australia and New Zealand; the USA alone (4.6% of the world’s population) represented 83% of the world’s oxycodone and 99% of hydrocodone consumption in the year 2009. Moreover, in the years 2007–2009, the average consumption of opioids was much higher in the USA than in any other European country: 39,487 defined daily doses per million inhabitants per day (DDD/MID) in the USA versus 20,000 in Canada, 19,000 in Germany, 16,000 in Austria and 13,000 in Denmark contrasted with 2000 DDD/MID in Portugal and, as an extreme example, with 50 DDD/MID in Africa [23] . ●●Rise of opioid prescriptions

From 2000 to 2010, the increase of opioid prescriptions in the USA was 400% [24] , 292% in Italy [25] , 65% in Great Britain [26] and 37% in Germany [27] . In Ontario (Canada), a substantial increase in the use and dose of opioids for nonmalignant pain was driven primarily by the use of long-acting oxycodone and to a lesser extent by fentanyl patches [28] . Thus, the rise


●●Opioid prescriptions for chronic pain

Forty six percent of persons with chronic pain in Kansas reported to have a current opioid prescription. A detailed analysis of persons with cancer and noncancer chronic pain regarding the use of opioids was not provided [22] . In a European survey, 23% of persons with chronic pain reported current treatment by weak opioids and 5% by strong opioids [29] . Two-thirds to three-fourth of opioid prescriptions in Denmark, Germany and Great Britain respectively were for patients with CNCP [26,30–31] . ●●Long-term opioid therapy for CNCP

The different definitions of LtOT do not allow an exact comparison of prevalence rates for opioid usage. In a nation-wide representative telephone community survey in the USA, conducted in 2001, 3.6% reported regular prescription opioid use [32] . National prescription tracking data estimated that LtOT for CNCP was initiated in 2% of US adults between 1997 and 2005 [33] . In two large US health plans, different age and gender groups exhibited a total percentage increase from 16 to 87% for incident long-term opioid use and from 61 to 135% for prevalent long-term opioid use for CNCP from 1997 to 2005. Prevalent long-term opioid use ranged between 1 and 9% in 2005, depending on the different gender and age groups [34] . In a Norwegian longitudinal study from 2006 to 2009, 3% of people with CNCP used opioids persistently [35] . The prevalence of LtOT for CNCP was 1.1% for men and 1.4% for women in a Danish survey conducted in 2005 [35] . The average prevalence of LtOT was 1.3% in a sample of a large German statutory health insurance between 2010 and 2012 [36] . We conclude from the data that are available, that the rates of LtOT in patients with CNCP are higher in North America than in Europe. ●●CNCP: indications for LtOT

The most frequent diagnoses associated with LtOT are diseases of the musculoskeletal

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10.2217/pmt.16.5

Perspective Häuser, Petzke, Radbruch & Tölle system and connective tissue (low back pain, osteoarthritis) both in North America and Europe [22,31,37] . ●●High-dose LtOT

The different definitions of high-dose opioid therapy impede the comparison of study results from different countries. In 2004, higher dose opioid therapy (≥100 mg/day MED) for chronic low back pain in US primary care settings occurred in 8.6% of patients who received opioids long-term (90+ consecutive days) [38] . High-dose opioid therapy (≥180 mg/day MED; 90+ consecutive days) was prescribed to 8.2% of veterans of an US regional healthcare network.). The average dose of MED in this group of patients was 325 mg/day [39] . 20.5% of Canadian socio-economically disadvantaged patients received high-dose (≥200 mg/day MED) or very-high-dose (≥400 mg/day MED) therapy in 2003 [28] . High-dose opioids (≥180 mg/day MED) were prescribed to 8.2% of veterans of an US regional healthcare network for 90+ consecutive days. The average dose of MED in the highdose group was 325 mg/day [39] , and 20.5% of patients received high-dose (≥200 mg/day MED) or very-high-dose (≥400 mg/day MED) prescriptions in 2003 in a Canadian study with socio-economically disadvantaged patients [28] . Twenty three percent of patients with CNCP in an UK primary care study were prescribed with dosages ≥100 mg/day MED [26] , and 15.5% of insureds with LTOT of a large German health statutory company were prescribed with dosages ≥100 mg/day MED with an average ME of 173 mg/day. The average percentage of patients with ≥180 mg/day MED per quarter was 5.2% between 2010 and 2012. There was no increase of the percentage of patients with high-dose prescriptions in a German sample [36] . We conclude that the rates of high-dose LtOT are obviously higher in North America than in Europe, especially in certain populations (veterans, socio-economically disadvantaged patients). Problematic use of prescribed opioids Problematic use of prescribed opioids can be categorized according to a recent consensus statement published by the Analgesic, Anesthetic and Addiction Clinical Trials, Translations, Innovations, Opportunities and Networks (ACTTION) [40] :

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●● Misuse: opioid use contrary to the directed or

prescribed pattern of use, regardless of the presence or absence of harm or adverse effects; ●● Abuse: intentional use of the opioid for a non-

medical purpose, such as euphoria or altering one’s state of consciousness; ●● Addiction: pattern of continued use with

experience of, or demonstrated potential for, harm (e.g., ‘impaired control over drug use, compulsive use, continued use despite harm and craving’). A recently conducted systematic review on the prevalence of opioid misuse, abuse and addiction in patients with chronic pain included 38 studies with samples of the general population and of different levels of care (primary care, pain clinics). Only two of these studies were conducted in Europe, the remaining ones were conducted in USA. The prevalence of problematic ranged from 1 to 81%, of misuse from between 21 and 29% and of addiction between 8 and 12% across all studies. Most notably, the rates of misuse and addiction were much higher in clinical than in nonclinical samples [41] . The rate of opioid addiction in a Danish pain clinic ranged between 14.4 and 19.3% [42] and was similar to the ones of US pain clinics. Of note, Denmark is known for its liberal opioid prescription in Europe [42] . The rate of misuse assessed in a Norwegian prescription database was 0.08–0.3% and thus much lower than the average misuse rates which were mainly gathered in pain clinics [43] . Only one of the US studies included into the systematic review was based on a community sample. The rate of misuse in this sample was 3.3% [44] . In contrast to the findings of the systematic review, the pooled 1-year prevalence of opioid prescription abuse (defined by hospital stays because of mental and behavioral disorders due to alcohol, opioids, tranquilizers, multiple substances and intoxications by narcotic agents) in a large German medical health insurance organization during the fiscal year 2012 was 0.008% [36] . The low prevalence rates of potential opioid abuse by German insureds are in line with findings from German pain clinics. Two case series of patients at a German tertiary care pain center demonstrated that problematic use and concealed use of other drugs were rare: in six of 121 patients with an LtOT of more than 3 years, an opioid detoxciation was performed due to concurrent use of benzodiazepines [45] .


The opioid epidemic & the long-term opioid therapy for chronic noncancer pain revisited The incidence of under-reported opioid use was 3% in 243 patients of a tertiary care pain clinic [46] . Of note, rates of misuse of prescribed opioids are typically lower in clinical opioid trials which excluded patients with major mental disorders including previous or known substance abuse. Behavior typical for addiction was not observed in two open-label studies comparing two different opioids over a year [47,48] . Only one of 11 open-label extension studies of placebo-controlled RCTs in CNCP syndromes (low back, osteoarthritis and neuropathic pain) systematically assessed opioid abuse. The study was conducted in the USA with oxycodone: 5.7% of the patients met the criteria of opioid abuse as assessed by the study investigators and 2.6% did so as reviewed by independent experts [12] . A Cochrane review on long-term (>6 months) opioid therapy included randomized controlled trials and pre–post-case series. Signs of opioid addiction were reported in 0.27% of participants in the studies that reported that outcome [49] . Predictors of problematic use of prescribed opioids Risk factors for problematic use of prescribed opioids in the USA included a family history of substance use disorder, serving time in prison, living in poor rural communities, battlefield injuries during war service, younger age, male gender, white race, multiple pain complaints, marked pain-related functional limitations, substance disorders or post-traumatic stress disorder [49–52] . In a Norwegian study, a strong association was observed between chronic pain and LtOT with the clustering of addictive behaviors such as daily smoking, high alcohol intake, illicit drug use in the past year, obesity and long-term use of benzodiazepines [42] . In a sample of a large German health statutory company, problematic opioid prescription use was associated with younger age, diagnoses of somatoform pain disorder and depression and with prescription of tranquilizers [36] . In summary, in USA as well as in European samples abuse of prescribed opioids by chronic pain patients is associated with mental disorders including substance disorder. Opioid prescription associated mortality In the USA, dramatic increases in the prescription use of opioid analgesics have been paralleled


Perspective

by alarming increases in rates of the abuse and intentional misuse of these drugs between 2000 and 2010. In 2010, the number of deaths related to opioid analgesics more than doubled the number of 2002 and and the number of deaths from heroin and cocaine deaths combined. The death rates associated with prescribed opioids declined from 2011 to 2013 [52] . The exact proportionate contribution to this increased mortality by actual illicit drug use of prescribed opioids by persons without chronic pain, (accidental) overdose in patients with chronic pain or an increased risk of mortality associated with regular opioid use as prescribed by a physician is not known [53] . Manchikanti [4] estimated that the majority of deaths (60%) occurred in patients with prescribed opioids based on prescribing guidelines by medical boards. In total, 20% of deaths occurred in low-dose opioid therapy of 100 mg of morphine equivalent dose or less per day and 40% of deaths occurred in those receiving morphine of over 100 mg per day. In contrast, 40% of deaths occurred in individuals abusing opioids obtained by multiple prescriptions, doctor shopping and drug diversion. The daily dose of morphine equivalent was strongly associated with opioid-related mortality in a Canadian population-based nested case–control study [54] . There is a paucity of studies on deaths associated with use of prescribed opioids in Europe. In Scotland, tramadol-related deaths increased from 8 in 2001 to 34 deaths in 2011 [55] . A Danish longitudinal study followed 13,127 persons from the 2000 and 2005 health surveys for up to 11 years. Long-term opioid users had a 1.72-times higher risk and individuals with chronic pain without opioid use had a 1.39-times higher risk of all-cause mortality compared with individuals without chronic pain. The association between long-term opioid use and cardiovascular and cancer mortality was not statistically significant [38] . Breivik and Stubhaug commented that it remains to be determined whether this higher mortality rate is caused by the opioid treatment or simply reflects the yet poorly defined long-term sequelae of the pain problem itself [56] . Taken together, there is no convincing evidence from European studies, that LtOT increases the mortality in patients with CNCP. However, there is robust evidence from cohort studies, that LtOT is associated with constipation, sleep-disordered breathing, fractures and sexual dysfunction [57] .


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Perspective Häuser, Petzke, Radbruch & Tölle The opioid epidemic: a North American, but not a European problem Breivik commented that in Scandinavia nothing is seen like the mega-numbers of prescription opioid overdose statistics in the USA, even despite similarly liberal use [56] . Probably the stable heathcare system in Scandinavia and the early awareness of harms of uncritical prescriptions of opiods for CNCP in Scandinavia [58,59] have prevented such an opioid misuse catastrophe that now is highly visible in the USA [32] and Canada [54] . Sullivan [32] discussed the following potential reasons for the opioid epidemic in USA: ●● Physician-related: influenced by pharma marketing; inadequate training on opioid pharmacology and risks; lack of access to multicomponent therapy; ease of prescribing opioids compared with other pain therapies; ●● Patient-related: Focus on pain rather than on

psychological distress as a treatment target; more value placed on pain relief than on functional improvement; ●● Society-related: Acceptance of the human

right to have access to pain treatment and interpretation of this right in terms of access to opioid therapy; better insurance coverage for medications than for psychological pain therapies; aggressive marketing of sustained opiods as ‘pain killers’ by pharmaceutical companies. In addition, the preference of opioids for CNCP might be triggered by the uncritically publicly distributed belief that opioids are the most potent painkillers in CNCP and that there is a type of CNCP which necessitates the use of an opioid CNCP [60] . Appraisal of the evidence of efficacy of long-term opioid therapy The US Health Technology Assessment report on LtOT found no study which compared opioids versus placebo, no opioid therapy or nonopioid therapy for long-term (defined by >1 year study duration) outcomes related to pain, function or quality of life [7] . However, this review did not evaluate studies with LtOT greater than 3 months, which would be appropriate according to the definition of LToT [2] . In addition, RCts of 4–12 weeks’ duration should be considered because the duration of trials as required by drug approval agencies ranges from 4 to 12 weeks.

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●●Short-term efficacy

A detailed analysis of the outcomes of recent meta-analyses of placebo-controlled RCTs with opioids in CNCP-syndromes with a study duration ≥4 weeks revealed that the benefits of opioids in reducing pain and disability in chronic osteoarthritis and low back pain are not consistent (see Table 1) [11,17] . For further details, please refer to Table 2 of [17] . The better tolerability of opioids compared with placebo in EERW (Enriched Enrolment Randomised Withdrawal) design studies compared with parallel and cross over design studies can be explained by the inclusion criteria of EERW studies (inclusion of patients with substantial pain relief and tolerable side effects in the open-label phase into the double-blind phase) [13,14] . ●●Long-term efficacy

A randomized trial of 6 months’ duration conducted in Norway involved 199 patients with chronic osteoarthritis pain. Transdermal 7-day buprenorphine flexible 5 or 10 or 20 μg/h was not significantly superior over placebo in reducing pain or subjective physical impairment (p = 0.06 for both) [61] . An open-label randomized controlled trial was conducted in several European countries. 675 patients with chronic low back pain (nociceptive, neuropathic or mixed) were included. Patients were treated with either transdermal fentanyl 25 μg/h or oral morphine 30 mg/day for 13 months. Thirty seven percent of the patients in the fentanyl group and 37% in the morphine group reported at the end of the treatment at least 50% improvement of pain at rest. 40 and 50%, respectively, reported an at at least 50% improvement of pain at movement. In both groups, physical functional ability improved significantly, from 29 to 37 on a 0–100 scale. 37% of patients in the fentanyl group and 31% in the morphine group dropped out of the study due to adverse events [47] . An open-label, randomized controlled trial of 52 weeks’ duration was conducted in several European countries. 1117 patients with chronic low back pain or osteoarthritis pain were treated with either tapentadol (200–500 mg/day) or oxycodone (40–100 mg/day). Mean of pain intensity (with standard error) decreased from 7.6 (0.05) at the beginning of the study to 4.4 (0.09) at the end of the study in the tapentadol group and from 7.6 (0.11) to 4.5 (0.17) in the oxycodone group, and 48.1% of the patients in the tapentadol group


The opioid epidemic & the long-term opioid therapy for chronic noncancer pain revisited

Perspective

Table 1. The efficacy, tolerability, and safety of opioid analgesics compared with placebo at the end of treatment (randomized, double-blind trials with parallel and crossover design, duration ≥4 weeks). Target variable

Studies/ Opioid vs Statistical measures of efficacy (95% CI) participants placebo (%) (n)

Number needed to treat for an additional benefit or harm (95% CI)

Chronic low back pain†

Mean pain intensity At least 50% relief of pain Marked or very marked global improvement Disability Drop-out rates due to adverse events Serious adverse events

6/2869 2/1492 2/1153

26.2 vs 21.0 48.6 vs 29.0

SMD: -0.29 (-0.37 to - 0.21); p < 0.00001; I² = 0 RD: 0.05 (0.01–0.10), p = 0.01, I² = 0 RD: 0.16 (-0.01–0.34); p = 0.07, I² = 92

11 (9–14) 19 (10–107) Not calculated

4/1895 6/2910 5/2509

21.2 vs 6.0 1.4 vs 0.8

SMD: -0.22 (-0.31 to -0.12); p < 0.0001]; I² = 0 RD: 0.12 (0.05–0.19), p = 0.0007, I² = 88 RD: -0.01 (- 0.00–0.02); p = 0.08; I² = 0

13 (10–17) 7 (6–8) Not calculated

16/6743 2/2709 3/2251

25.1 vs 25.7 50.0 vs 37.8

SMD: -0.22 (-0.28 to -0.17); p < 0.00001; I² = 21% RD: -0.01 (-0.07–0.06) p = 0.82, I² = 75% RD: 0.13 (0.05–0.21); p = 0.002; I² = 74%

13 (10–17) Not calculated 8 (6–12)

14/5887 14/6457 11/5520

25.6 vs 7.0 2.4 vs 1.8

SMD: -0.22 (-0.28 to -0.17); p < 0.00001; I² = 0% RD: 0.17 (0.14–0.21), p < 0.00001, I² = 77% RD: 0.00 (- 0.00–0.01); p = 0.37; I² = 2%

11 (9–14) 5 (4–6) Not calculated

Chronic osteoarthritis pain‡ Mean pain intensity At least 50% relief of pain Marked or very marked global improvement Disability Drop-out rates due to adverse events Serious adverse events

Drugs tested: buprenorphine, oxycodone, tapentadol and tramadol. Drugs tested: buprenorphine, codeine, fentanyl, hydromorphone, morphine, oxycodone, oxymorphone, tapentadol and tramadol. RD: Risk difference; SMD: Standardized mean difference. Reproduced from [17].

† ‡

and 41.2% of the patients in the oxycodone group reported to be much or very much improved. Twenty three percent of patients in the tapentadol and 37% of patients in the oxycodone group dropped out due to side effects [48] . A systematic review (search of literature until December 2013) included 11 open-label extension studies of placebo-controlled RCTs. Twothousand-four-hundred and forty-five patients with nociceptive pain (back pain, osteoarthritis pain) and neuropathic pain (radiculopathy, polyneuropathy) were analyzed. Median study duration was 26 weeks (range: 26–108 weeks), and 28.5% of patients which were initially randomized, completed the open-label phase; 4.9% terminated the open-label period prematurely because of inadequate pain relief, 16.8% dropped out the open-label period prematurely due to adverse effects, 4.9% of patients dropped out due to lack of efficacy and 0.08% of patients died during the open-label period. Mean pain intensity did not significantly change (p = 0.50) between the end of the randomized period and the end of the open-label phase. However, the harms (abuse of prescribed opioids, mortality) of LtOT in clinical practice may be underestimated by long-term extension studies: these studies


excluded patients with major medical diseases and mental disorder. In addition, the study context is different from clinical practice in terms of the amount of monitoring, the experience of the physicians and their willingness to respond to patient complaints. Moreover, the positive effects of opioids in long-term open-label studies cannot be disentangled from those of: cotherapies which were not controlled for; unspecific (placebo) effects and spontaneous recovery of the lack of a control group without opioids [12] . A prospective, population-based study conducted in the USA included low back injured workers. Morphine equivalent dose (MED) increased significantly over 1 year. A minority of workers reported clinically meaningful improvement of pain and physical function [62] . In summary, there is robust evidence that some patients with chronic low back, osteoarthritis and neuropathic pain experience a sustained pain reduction and/or improvement of physical functioning by short-term and LtOT. Good clinical practice: guidelines recommendations Two recent systematic reviews of international guidelines on opioids for CNCP concluded [63,64]


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Perspective Häuser, Petzke, Radbruch & Tölle that despite some differences in the focus and in the amount of details of the practice guidelines across different countries and specialities, the following general principles how to initiate, continue and terminate opioid therapy were noted across all guidelines. Some major recommendations of the Canadian, German and US guidelines are outlined in Table 2.

functioning relevant for the patient as a realistic treatment goal [11,19] . All guidelines stressed that monotherapy with opioids should be avoided and a multicomponent therapy should be performed. Only the German guidelines specified potential indications and definite contraindications by ICD-10 codes and/or clinical pain diagnoses [11,17] (see next section).

●●Patient selection & risk stratification

A diligent medical assessment including psychosocial risk factors of potential drug abuse, should be performed as part of the initial assessment of a patient with CNCP. The German guidelines recommended a screening for any psychological distress as well [11] . Prior to initiating therapy, patients should be adequately informed about the benefits and risks of opioid therapy including driving ability. Obtaining written and signed informed consent prior to initiating therapy may be appropriate in some cases. Treatment expectations should be explored and individual goals of therapy should be defined together with the patient. The Canadian and German guidelines defined an at least 30% pain reduction and/or improvement of daily

●●Initiation & titration

The selection and dosage of opioids should be tailored to the individual response of the patient. Therapy should be started with the minimum dose required to achieve relief of pain and/or improved functioning wihout clinically relevant adverse effects. The dose should be subsequently increased according to patient response and tolerability. The Canadian guidelines provided detailed information on how to start and increase the dosage of the opioid. Once therapy is initiated, the patient must be closely monitored for loss of response, adverse events or aberrant drug-related behavior. The German guidelines provided practice tools for the treatment of opioid-induced nausea and constipation [11] .

Table 2. Comparison of the Canadian, German and US guidelines on long-term opioid therapy for chronic noncancer pain on selected parameters. Recommendations

American Pain Society and American Academy of Pain Medicine 2009

Canadian Practice Guidelines 2010

German Pain Society 2015

Comprehensive evaluation Psychosocial screening for mental disorders including substance abuse Exploring treatment expectations, defining goals of therapy Potential indications and contraindications by ICD-10 code Optimal starting dose

Yes Substance abuse

Yes Substance abuse

Yes

Yes

Yes Any mental disorder including substance abuse Yes

No

No

Yes

Based on individual assessment

Based on individual assessment

Duration of trial of opioid therapy

For several weeks to months

Regular assessment Daily dosages morphine equivalent requiring particular caution Indications for discontinuation of opioid therapy Drug holiday Special situations

Yes 200 mg/day

Detailed stepped approach described in guideline Detailed stepped approach described in guideline Yes 200 mg/day

Yes

Yes

Yes

No Mental disorders including substance abuse

No Mental disorders including substance abuse; adolescents; pregnancy; seniors

Yes Mental disorders including substance abuse; adolescents; pregnancy; seniors

Up to 12 weeks Yes 120 mg/day

Data taken from [11,18,19].

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The opioid epidemic & the long-term opioid therapy for chronic noncancer pain revisited ●●Continuation

The German guidelines clearly stated, that LtOT should only be performed in ‘responders’, defined by the achievement of the individual treatment goals without or minor side effects [11] . Regular reassessment (pain intensity and level of functioning, presence of adverse events, adherence to prescribed nonpharmaclogical therapies, abberant drug behavior). ●●Discontinuation

Serious or repeated aberrant drug-related behaviors or diversion, experience of intolerable adverse effects or failure to maintain/achieve therapeutic goals are indications for discontinuation. All guidelines contained more or less detailed information for special situations, for example, adolescents and elderly or geriatric patients. The German guidelines recommended that after 6 months of opioid therapy, the possibility of dose reduction and/or a trial discontinuation should be discussed also with patients with a documented treatment response, in order to assess the indication for continuation of treatment and the potential response to the nondrugbased therapeutic measures initiated in parallel (e.g., multimodal therapy) [11] . Defining indications & contraindications for long-term opioid therapy of noncancer pain: untying chronic noncancer pain ●●Potential indications

The term ‘CNCP’ comprises a great variety of pain syndromes ranging from chronic pain syndromes with defined structural pathology to mental disorders with the main symptom chronic pain. One problem with the rise of the prescription rates of opioids in the last decade might be caused by the fact that all types of CNCP were considered to be equally opioid sensitive. Some experts in pain medicine even claimed that there is an ‘opioid demanding’ CNCP [60] . However, prescriptions of opioids for different types of CNCP should be evidence-based and not an (unfortunately) unrealistic wish for pain relief. The IASP Special Interest Group (SIG) on Systematic Reviews in Pain Relief and the Cochrane Pain, Palliative and Supportive Care Systematic Review Group editors suggested, that the reliable sample size for efficacy for an individual study is ≥200 participants/per study arm [65] . The reliable sample size for efficacy for meta-analysisis is similarly considered to be ≥400 participants [37] . Only three types of CNCP,


Perspective

namely chronic osteoarthritis pain, chronic low back pain and chronic diabetic polyneuropathy pain have met these criteria until now [11,17] . On the other end of the spectrum, only one RCT with a total of less than 60 patients is available for the following conditions: stump/phantom pain, lumbar root pain and neuropathic pain after spinal cord injury with inconsistent benefits of opioids over placebo (see Table 3) [15] . Contraindications Based on expert consensus and cohort studies, the LONTS update defined contraindications of LtOT in CNCP (see Table 4 ) [11] . Of note, patients with these disorders were excluded by the majority of RCTs with opioids in CNCP [13–15] . A trial with opioids in a patient with nociceptive and/or neuropathic pain and a comorbid mental disorder can be undertaken. The major contraindications are somatoform pain disorders and functional somatic syndromes with the key symptom pain such as irritable bowel syndrome and fibromyalgia. The data on characteristics of patients receiving LtoT for CNCP in clinical practice settings and the associated problems outlined above raise the question, if these patients have met these contraindications. Longitudinal administrative data from a US national, commercially insured population and Arkansas Medicaid enrollees were analyzed. In 2000, among individuals with CNCP, LToT was more common among those with a mental disorders or substance abuse disorders than among those without, both in commercially insured (8 vs 3%) and Arkansas Medicaid (20 vs 13%) populations. Between 2000 and 2005, rates of LToT increased by 34.9% among individuals with a mental disorder or substance abuse and by 27.8% among individuals without these disorders in the commercially insured population. In Arkansas Medicaid patients, chronic opioid use increased by 55.4% among individuals with a mental disorder or substance abuse and by 39.8% among those without [66] . The association of LtOT for CNCP with mental disorders has also been demonstrated in community-based samples in Canada [28] and Denmark [58] too. The major pain location for which opioids were prescribed in the USA was low back pain [67] . Of note, the diagnostic label ‘low back pain’ includes different types of pain syndromes extending from nonspecific low back pain without obvious structural changes to specific low back pain (e.g., radiculopathy, multiple


10.2217/pmt.16.5

Perspective Häuser, Petzke, Radbruch & Tölle Table 3. Number of studies/participants and trial duration of randomized controlled placebo-controlled trials in different types of chronic noncancer pain (search of literature until October 2013). Type of chronic noncancer pain

Studies/participants (n)

Trial duration weeks (minimum–maximum)†

Osteoarthritis Low back Diabetic polyneuropathy Postherpetic neuralgia Postamputation (stump and phantom pain) Lumbar root pain Neuropathic pain after spinal cord injury

20 RCTs, 8545 patients 12 RCTs, 4375 patients 4 RCTs, 580 patients 3 RCTs, 358 patients 1 RCT, 60 patients 1 RCT, 56 patients 1 RCT, 45 patients

4–26 4–16 4–12 4–6 6 5 6

The systematic review included only RCTs with a duration ≥4 weeks. RCT: Randomized controlled trial. Data taken from [13–15,17]. †

osteoporotic vertebral fractures [13] . Up to 20% of patients diagnosed with nonspecific low back pain met the criteria of a somatoform pain disorder [68] . In summary, pain treatment with opioids should only be considered in patients with a clearly defined nociceptive and/or neuropathic pain syndrome but not in patients with functional somatic syndromes/somatoform disorders and other mental disorders with the major symptom pain. Opioids in CNCP syndromes: first line, second line, third line, never ? A systematic review of randomized head-to-head comparisons of opioids versus other analgesics (study duration ≥4 weeks) did not find a significant difference between opioids, antidepressants and anticonvulsants (four RCTs, 223 patients) in efficacy, tolerability and safety. NSAIDs were superior to tramadol (four RCTs, 2572 patients) in efficacy and tolerability but not in safety in osteoarthritis pain [16] . Because of the paucity of direct head-to-head comparisons of drugs and drugs with nonpharmacological therapies in most CNCP syndromes, recommendations for first-, second- and third-line therapies can only be based on network meta-analyses or indirect evidence (e.g., number of studies, consistency of study findings; balancing potential benefits and harms; ease of use) and expert consensus. Alternative drugs to opioids with a high level of evidence (meta-analyses of RCTs) are antidepressants, anticonvulsants and with lower level of evidence the cannabinoids in neuropathic pain syndromes [69] , local [70] and systemic NSAIDs [71] for osteoarthritis pain and antidepressants and NSAIDs for chronic low back pain [72] . The revised consensus statement from

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the Canadian Pain Society based the recommendations for the management of chronic neuropathic pain on the degree of evidence of analgesic efficacy, safety and ease of use. Gabapentin and pregabalin, tricyclic antidepressants and serotonin/noradrenaline reuptake inhibitors were recommended for first-line, tramadol and controlledrelease opioid analgesics were recommended for second-line and cannabinoids (nabiximole) were recommended for third-line treatments of moderate-to-severe pain [69] . The American College of Rheumatology strongly recommended nonpharmacological therapies for the management of osteoarthritis of the hip and knee, such as aerobic, aquatic and/or resistance exercises, as well as weight loss for overweight patients. Acetaminophen, oral and topical NSAIDs (in combination with a proton pump inhibitor) and intra-articular corticosteroid injection were conditionally recommended for first-line pharmacological management of patients with knee OA. Intra-articular hyaluronate injections, duloxetine and opioids were conditionally recommended for second-line therapy. Opioids were strongly recommended for patients who were either not willing to undergo or had contraindications for total joint arthroplasty after the failure of firstand second-line drug therapies [73] . The ACR recommendations for osteoarthritis demonstrate that the whole clinical situation of a patient must be considered in case of treatment decisions. Clearly, opioids are neither a standard first line nor a standard last line (if all other treatments have failed). The LONTS update recommended that in the context of participatory decision making, the possible risks and benefits of treatment with opioid-containing analgesics compared with other drug-based and nondrug-based


The opioid epidemic & the long-term opioid therapy for chronic noncancer pain revisited treatment options should be discussed with the patient. The selection of the pharmacotherapy should consider the chronic pain syndrome in question, the patient’s comorbidities, potential contraindications, the patient’s preferences, benefits and harmful effects of previous treatments as well as the risk–benefit profiles of drug-based and nondrug-based treatment alternatives [11,17] . The evidence for the short-term efficacy of gabapentinoids and antidepressants as alternatives to opioids in chonic neuropathic pain is robust [69] . The data on long-term efficacy and safety of gabapentinoids and antidepressants in chronic neuropathic pain are as sparse as the ones for opioids. In contrast, there are no pharmacological alternatives to opioids with high-level evidence of efficacy and safety for musculoskeletal pain, especially in elderly patients with major medical diseases. Paracetamol is ineffective in the treatment of low back pain and provides minimal short-term benefit for most people with osteoarthritis [74] . Lack of long-term data, inadequate reporting of safety data, possible publication bias and few head-to-head comparisons limited the conclusions of a network meta-analysis comparing acetaminophen, NSAIDs, intra-articular corticosteroids, intra-articular hyaluronic acid and placebo [75] . The negative impact of NSAIDs on mortality and morbidity in elderly patients with major medical comorbidities has been repeatedly highlighted [76,77] .

Perspective

Conclusion There is a broad consensus in the pain community that the opioid epidemic in North America should be controlled and terminated and that Europe should be protected from it. In our opinion, this goal should not be achieved by overcritically disputing the long-term efficacy and safety of opioids in chronic low back pain and osteoarthritis pain and some neuropathic pain syndromes (e.g., diabetic polyneuropathy). Chou et al. required longterm (>1 year) outcomes related to pain, function or quality of life for opioids compared with placebo or any other treatment [7] . These data are likewise not available for any other drug treatment options in CNCP. The 2014 position paper of the American Academy of Neurology, which stated that there is no substantial evidence for maintenance of pain relief or improved function over long periods of time without incurring serious risk of overdose, dependence or addiction, might be valid for USA, but not for the European experience and data [53] . Opioid analgesics remain an important option for the drug treatment of carefully selected patients with chronic osteoarthritis pain, low back pain and neuropathic pain. LtOT of CNCP should not be expanded incautiously and unthinkingly; but in face of the existing data it must also not be categorically rejected, either. Opioids are clearly not a panacea for CNCP [78] . LtOT of unspecific functional pain syndromes (e.g., fibromyalgia) and of mental disorders with

Table 4. Contraindications to long-term treatment with opioid analgesics of the German guidelines on opioids in chronic noncancer pain. Condition

Evidence level Strength of Strength of (Oxford) recommendation consensus

Primary headache Functional disorders Fibromyalgia syndrome† Chronic pain as a major manifestation of a mental disorder (atypical depression, persistent somatoform pain disorder, generalized anxiety disorder, post-traumatic stress disorder) Chronic pancreatitis‡ Chronic inflammatory bowel disease‡ Comorbid severe affective disorder and/or suicidality Current medication abuse or passing on of medications to unauthorized persons, and/or serious doubt concerning responsible use of opioid analgesics (e.g., uncontrolled taking of medications and/or unwillingness or inability to adhere to the dosing schedule) Current or planned pregnancy

3b 5 4b 5

CCP CCP Negative CCP

Strong consensus Strong consensus Consensus Consensus

2b 3b 5 5

Negative Negative CCP CCP

Strong consensus Strong consensus Strong consensus Strong consensus

5

CCP

Strong consensus

Classification of consensus: Strong consensus: agreement of >95% of members; Consensus: agreement of >75–95% of members. † Exception: tramadol (also inhibits serotonin and norepinephrine reuptake); evidence level 2b, open recommendation (can be considered as a treatment option). ‡ Treatment for a limited time (