Portal de Periódicos da CAPES

Opioids for chronic non-cancer pain

2018; Elsevier BV; Volume: 18; Issue: 11 Linguagem: Inglês

10.1016/j.bjae.2018.06.006

2058-5357

H. W. Gallagher, David Galvin,

Musculoskeletal pain and rehabilitation

Learning objectivesBy reading this article you should be able to:•Identify criteria suggesting substance use disorder.•Discuss the adverse effects of long-term opioid therapy.•Describe morphine milligram equivalence (MME).•Explain the responsibilities of both the doctor and patient if an opioid trial is decided upon and commenced.Key points•2% of Europeans have an opioid use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria.•There is little evidence for using opioids as therapy for chronic, non-cancer pain beyond 16 weeks’ duration.•Guidelines are available describing multimodal approaches to chronic pain management; advice on opioid trials; risk–benefit analysis; identification of risk factors for harm or misuse; and treatment of addiction and overdose.•Opioids may be indicated for chronic painful diabetic neuropathy, and elderly patients with osteoarthritis of the back and knee. By reading this article you should be able to:•Identify criteria suggesting substance use disorder.•Discuss the adverse effects of long-term opioid therapy.•Describe morphine milligram equivalence (MME).•Explain the responsibilities of both the doctor and patient if an opioid trial is decided upon and commenced. •2% of Europeans have an opioid use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria.•There is little evidence for using opioids as therapy for chronic, non-cancer pain beyond 16 weeks’ duration.•Guidelines are available describing multimodal approaches to chronic pain management; advice on opioid trials; risk–benefit analysis; identification of risk factors for harm or misuse; and treatment of addiction and overdose.•Opioids may be indicated for chronic painful diabetic neuropathy, and elderly patients with osteoarthritis of the back and knee. The global epidemic of abuse of opioids prescribed for chronic, non-cancer pain shows no sign of abating. The rate of increase in opioid prescriptions in the past 30 yr has been most evident in the USA, but figures from Europe and Australia also show a similar trend. The limited evidence of efficacy of opioids in many chronic pain states, the lack of knowledge of the long-term effects of opioids amongst medical professionals, combined with the increased occurrence of addiction and fatal and non-fatal overdose, suggests that opioids should not be a first-line treatment option. However, they should not be relegated to a treatment of last resort for certain patients with chronic non-cancer pain. Prescribing and clinical efficacy should be closely monitored and regularly reassessed. A meta-analysis of chronic pain in the UK suggested prevalence’s of 35–51% for all severities of chronic pain and 10–14% for severe chronic pain. The prevalence in those aged 18–39 yr was up to 30%, chronic pain being more common in females than in males.1Fayaz A. Croft P. Langford R.M. et al.Prevalence of chronic pain in the UK: a systematic review and meta-analysis of population studies.BMJ Open. 2016; 6: e010364Crossref PubMed Scopus (546) Google Scholar Although the understanding of the mechanisms of pain has improved, treatment successes tend to be patient-specific. This is most likely because of the complex aetiology of chronic pain and the differences in assessment of a successful outcome from the perspectives of the patient and the doctor. This high prevalence of chronic pain in conjunction with the limited number of successful treatment options has contributed to the corresponding increase in opioid prescribing. The acute and medium-term adverse effects of opioids are well known. Opioids alleviate pain in the short term, but they can cause sedation, dizziness, nausea, vomiting, constipation, respiratory depression, and tolerance. These effects are dose-dependent and reversible on withdrawal of the opioid medication. The impact on society of long-term opioid therapy is also being seen, with increases in criminal behaviour. Substance use disorder is defined by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as a ‘problematic use of a substance, which results in impairment in daily life or noticeable distress’.2American Psychiatric Association Diagnostic and statistical manual of mental disorders: DSM-5.5th ed. APA, Arlington, VA2013Crossref Google Scholar The DSM-5 has described 11 criteria, which are required for a diagnosis of opioid use disorder: the presence of 2–3 criteria suggests mild disorder, 4–5 suggests moderate disorder, and 6–7 or greater suggests severe disorder. The criteria are as follows2American Psychiatric Association Diagnostic and statistical manual of mental disorders: DSM-5.5th ed. APA, Arlington, VA2013Crossref Google Scholar:•Taking the opioid in larger amounts and for longer than intended.•Wanting to cut down or quit but not being able to do it.•Spending a lot of time obtaining the opioid.•Craving or a strong desire to use opioids.•Repeatedly unable to carry out major obligations at work, school, or home because of opioid use.•Continued use despite persistent or recurring social or interpersonal problems caused or made worse by opioid use.•Stopping or reducing important social, occupational, or recreational activities because of opioid use.•Recurrent use of opioids in physically hazardous situations.•Consistent use of opioids despite acknowledgment of persistent or recurrent physical or psychological difficulties from using opioids.•Tolerance may develop with chronic opioid use. This is a decreased response to the same dose of a drug. It is known adverse effect of long-term opioid therapy for which dose adjustment may be required. Tolerance to both the sedative effects and the analgesic effects may both occur.•A withdrawal syndrome may be precipitated by abrupt cessation, rapid dose reduction, reduced blood levels, the administration of an antagonist, or both. It is estimated that approximately 22.8 million Europeans use prescription opioid medication with an estimated 445,000 (2%) having an opioid use disorder.3Alho H. Prevalence of prescription opioid-dependency in Europe and risk factors for abuse. International Society of Addiction Medicine, 2013https://pdfs.semanticscholar.org/acc9/c2ffd5401f09a5471a450bd7ff4c80ed64f7.pdfDate accessed: May 3, 2018Google Scholar The diagnosis of an opioid use disorder in a patient with chronic pain is very difficult, with some studies suggesting a prevalence as high as 20–25%.4Vowles K. McEntee K. Julnes P.S. Frohe T. Ney J.P. van der Goes D.N. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis.Pain. 2015; 156: 569-576Crossref PubMed Scopus (721) Google Scholar Despite the widespread prescribing of opioids for chronic pain, there is a lack of evidence of improvement in chronic pain when a patient receives long-term opioid therapy. Placebo-controlled trials comparing opioid therapy with no therapy, or non-opioid therapy lasting up to 12 weeks have been performed.5Chou R. Turner J.A. Devine E.B. et al.The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop.Ann Intern Med. 2015; 162: 276-286Crossref PubMed Scopus (1022) Google Scholar However, the vast majority of trials for opioid therapy are for 6 weeks or less. Most of the positive published data appear to be in the patients with painful diabetic neuropathy. Long-term studies of the effectiveness of opioid use greater than 12 weeks are lacking, and more research is needed into long-term opioid therapy for chronic pain and its subsequent effects. There is also a lack of evidence regarding the effectiveness of opioid therapy in improving physical function in patients with chronic pain. Many observational trials have been performed but have drawn no definitive conclusions about functional improvement. This appears to be mainly because of significant dissatisfaction amongst patients caused by inadequate pain relief, but also the heterogeneity of the chronic pain conditions studied and patients’ difficulties with functional evaluation. Observational trials have also shown that long-term opioid use is associated with an increased risk of accidental overdose, opioid abuse, dependence, fractures (particularly hip and upper limb), and myocardial infarction.6Raghavan S. Harvey A.D. Humble S.R. New opioid side effects and implications for long-term therapy.Curr Anaesth Crit Care. 2011; 1: 18-21Crossref Scopus (16) Google Scholar Other effects of long-term opioid therapy have been described in recent years. These include hypogonadism, osteoporosis, immune suppression, cognitive impairment, and opioid-induced hyperalgesia (OIH). The risks of addiction and overdose remain a problem, although addiction may not be the key risk in long-term opioid users. Continued use of opioids despite harm is a major concern. A difficulty arises when a patient has a failed opioid trial but remains on opioids with the associated risk outweighing any benefit. The lack of an exit strategy for these patients remains a major issue and encourages the focus of treatment to shift to other options involved in the multidisciplinary approach. Also, the risk of drug diversion is a major public health and societal concern that results in increased healthcare costs, and alteration and derailment of treatment plans.7Kraus M. Lintzeris N. Maier C. et al.Recommendations for the prevention, detection, treatment and management of prescription opioid analgesic dependence: outcomes from the Opioid Analgesic Dependence Education Nexus (OPEN) meeting.Int J Ment Health Addict. 2016; 14: 313Crossref PubMed Scopus (14) Google Scholar OIH is defined as a decrease in the nociceptive threshold caused by exposure to opioids. It can be mistaken for tolerance and can lead to dose escalation of the prescribed opioid, which can worsen the patient's pain through pronociceptive mechanisms. It is acknowledged that making the distinction between OIH and tolerance can be very difficult. The exact mechanism and location of OIH is uncertain, but five mechanisms have been suggested: changes in the central glutaminergic system mediated by activation of N-methyl-d-aspartate (NMDA) receptors; increased spinal dynorphins; activation of descending pathways; genetic mechanisms; and decreased neurotransmitter reuptake and enhanced nociceptive responses.8Lee M. Silverman S.M. Hansen H. et al.A comprehensive review of opioid-induced hyperalgesia.Pain Physician. 2011; 14: 145-161Crossref PubMed Google Scholar The Surgeon General in the USA introduced a campaign in 2016 called ‘Turn the Tide Rx’. This campaign is aimed at primary care practitioners and invites them to take a pledge to help end the opioid crisis. The need for such a campaign was indicated by the large increase in the prescription of opioids for chronic pain conditions, outside of end-of-life and cancer care treatment programmes, and also by the rapid increase in numbers of fatalities caused by accidental overdose over the past 20 yr; opioids were involved in 63% of drug overdoses in the USA in 2015. Half of these overdoses involved a prescribed opioid. The prescription of opioids in the USA quadrupled between 1999 and 2010. The number of opioid-associated deaths since 1999 has also quadrupled.9CDCWide-ranging online data for epidemiologic research (WONDER). CDC, National Center for Health Statistics, Atlanta, GA2016http://wonder.cdc.govDate accessed: May 3, 2018Google Scholar In 2012, 259 million prescriptions were written for opioids medication in the USA, almost one prescription per person. The rate of prescriptions per 100 persons varied from 72 to 80 in the years 2006–2015. The amount of opioid prescriptions has increased 3-fold from between 1999 and 2015 with a peak in 2010 in the US. Morphine milligram equivalents (MME) per day is a tool used to assign a value to opioids to represent their relative potencies. The aim of this tool is to allow conversion from one opioid to another. However, there are multiple issues surrounding MME conversion, and various conversion tables exist. The lack of an internationally accepted opioid conversion method may result in underdosing or accidental overdose when rotating from one opioid to another. Opioids display different pharmacokinetics at different doses, for example methadone accumulates when the dosing interval is less than the elimination half-life. The half-life of methadone can vary from 8 to 59 h with large inter-individual variability. In comparison, the analgesic effect of methadone is 6–8 h, resulting in possible accumulation if the dosing interval is too frequent. Respiratory depression and cardiac arrest may result. The MME per day per capita in the USA was 670 mg in 2011. In Europe, peak opioid consumption occurred in 2010 with a daily MME per capita of 170 mg. The UK experienced a peak in MME of just greater than 800 mg per capita in 2010; in Germany the peak was 600 mg MME per capita in 2013; in France an MME of just below 250 mg per capita was recorded in 2013. Opioid consumption in Australia has also increased, with an MME of 500 mg per capita in 2014. Corresponding figures for Ireland were just below 350 mg MME per capita in 2012 and just above 350 mg MME per capita in 2014.10Novak S.P. Håkansson A. Martinez-Raga J. Nonmedical use of prescription drugs in the European Union.BMC Psychiatry. 2016; 16: 274Crossref PubMed Scopus (109) Google Scholar Other European statistics are similar, with 5–7% of all patients entering drug treatment programmes in Europe reporting prescription opioids as their primary drug, and around 10 million people receive regular prescriptions for opioid analgesics. There has been a 400% increase in prescriptions for opioids in the past 10 yr. The number of opioid prescriptions in England increased 5-fold (from 3 million to 15 million prescriptions) between 1991 and 2009.11Hay G, Rael dos Santos A, Worsley J . Estimates of the prevalence of opiate use and/or crack cocaine use in England, 2011/12. Centre for Public Health, LiverpoolGoogle Scholar In the same study, tramadol was prescribed almost twice as frequently as any other opioid. Opioids (including heroin) were associated with 64% of drug-related deaths in the UK in 2015 (Table 1).12Deaths related to drug poisoning in England and Wales: 2015 registrations; Office of National StatisticsGoogle Scholar A retrospective cohort study published in 2016 showed that 91% of those who previously overdosed on opioids were represcribed opioids; 7% of these patients had a repeat overdose.13Larochelle M.R. Liebschutz J.M. Zhang F. Opioid prescribing after nonfatal overdose and association with repeated overdose: a cohort study.Ann Intern Med. 2016; 164: 1-9Crossref PubMed Scopus (122) Google Scholar Trends in the developing world are 20 yr behind the USA and Europe, with opioid prescribing for chronic pain on the increase.Table 1Number of drug-related deaths registered in England and Wales 2012–2016 where selected substances were mentioned on the death certificate.12Deaths related to drug poisoning in England and Wales: 2015 registrations; Office of National StatisticsGoogle ScholarSubstanceNumber of deaths per year20122013201420152016All drug poisoning deaths2,5972,9553,3463,6743,744Any opioid∗1,2901,5921,7861,9892,038 Heroin and/or morphine5797659521,2011,209 Methadone414429394434413 Tramadol175220240208184 Oxycodone3751515175 Fentanyl2222403458Cocaine139169247320371Any amphetamine97120151157160Any new psychoactive substance556382114123Any benzodiazepine284342372366406Pregabalin4333890111Gabapentin89264959All antidepressants468466517447460Paracetamol†182226200197219Propranolol3946545545Cause of death defined using the International Classification of Diseases, Tenth Revision (ICD-10). Figures are for deaths registered, rather than deaths occurring in 2012–2016 and include deaths of non-residents. ∗Figures for opioids exclude opioids contained in a paracetamol compound, that is, co-codamol, codydramol, and coproxamol. †Figures exclude dextropropoxyphene mentioned without paracetamol. Open table in a new tab Cause of death defined using the International Classification of Diseases, Tenth Revision (ICD-10). Figures are for deaths registered, rather than deaths occurring in 2012–2016 and include deaths of non-residents. ∗Figures for opioids exclude opioids contained in a paracetamol compound, that is, co-codamol, codydramol, and coproxamol. †Figures exclude dextropropoxyphene mentioned without paracetamol. In response to the international crisis concerning opioid prescriptions, many countries have produced guidelines and advisory documents on the approach to chronic pain management and the safe prescribing of opioids for non-cancer pain, as it is recognised that only a small group of chronic pain patients will benefit from chronic opioid therapy. The US Center for Disease Control and Prevention (CDC) issued guidelines in March 2016 regarding initiation or continuation on opioid medications.14Dowell D. Haegerich T.M. Chou R. CDC guideline for prescribing opioids for chronic pain — United States, 2016.MMWR Recomm Rep. 2016; 65: 1-49Crossref PubMed Scopus (2024) Google Scholar These guidelines are condensed in a pocket card for opioid prescribing, summarised in Table 2.15Turn the Tide Rx Prescribing opioids for chronic pain.https://turnthetiderx.org/wp-content/uploads/2016/06/TurnTheTide_PocketGuide_Final.pdfDate accessed: May 3, 2018Google ScholarTable 2Turn The Tide Rx: opioid prescribing for chronic rain. Adapted from https://turnthetiderx.org/wp-content/uploads/2016/06/TurnTheTide_PocketGuide_Final.pdf.1. Before prescribing•Assess pain and function.•Consider if non-opioid therapies are appropriate.•Talk to patients about treatment plan.•Evaluate risk of harm or misuse.2. When you prescribe•Start low and go slow.•Commence immediate release opioids for the shortest therapeutic duration.•Arrange frequent follow-up for patients on 50 MME day−1 or more or those who may have risk factors.3. After initiation of opioid therapy•Regularly assess the benefits.•Tailor and taper the dose.•Continue therapy after a successful trial period.4. Treating overdose and addiction•Regularly screen for opioid use disorder.•Considering offering naloxone for at-risk patients.MME, morphine milligram equivalence. Open table in a new tab MME, morphine milligram equivalence. The Faculty of Pain Medicine (FPM) in the UK launched a resource called ‘Opioids Aware’ for both patients and healthcare professionals to promote the safer prescribing of opioids. It aims to reinforce prescribing by the application of best practice: ensuring understanding of the condition, the patient and their context, and understanding the clinical use of the drug.16Opioids Aware A resource for patients and healthcare professionals to support prescribing of opioid medicines for pain.https://www.rcoa.ac.uk/faculty-of-pain-medicine/opioids-awareDate accessed: May 3, 2018Google Scholar The FPM resource provides information on opioids and the law, opioid prescribing guidelines, importance of accurate record-keeping, the importance of patient assessment before commencing opioids to identify potential for addiction or tolerance, long-term opioids and their adverse effects, how to perform an opioid trial, opioid equivalents, and information on stopping opioid therapy. The resource also provides information for patients commencing opioid therapy, including information on chronic pain, the options available to them, and a list of frequently asked questions and answers. The importance of clinical record keeping is highlighted in the FPM guideline. Records should include:(i)Clinical findings that support the decision to prescribe opioids.(ii)The intended outcomes of opioid therapy, as discussed and agreed with the patient.(iii)The choice of drug, formulation, dose, and duration of treatment.(iv)A clear account of how, when, and in what circumstances the dose of drug should be adjusted. This should also be given to the patient. It is very important to discuss and agree with the patient when opioid therapy should be discontinued. Ideally, the patient should bring someone with them for the consultation before starting opioids. This will allow for discussion around acute illness and reiterate the awareness needed if the patient becomes acutely unwell but remains taking the same dose of opioids. Education about naloxone, in the case of a suspected opioid overdose, can also be given. The use of guidelines without evidence-based research can have its own limitations. This is seen in the topic of long-term opioid therapy. No studies beyond 12 weeks of treatment with opioids exist, which means the guidelines offered are based on expert opinion and clinical experience. The presence of guidelines means the decision to refer from a family doctor to a pain medicine physician may become less clear as rigidly adhering to the guidelines may still pose a risk to a patient regardless of how ‘low’ their opioid dose is. The need for continuous assessment of risk–benefit is more important than strictly adhering to the guidelines and not recognising the risk associated with any opioid dose. The dose of 90 mg MME day−1 is simply a level above which the risk has been measured and deemed high. A risk exists at all doses, and this risk increases as the dose increases. Furthermore, the guidelines cannot take into consideration any pre-existing conditions such as old age, respiratory diseases, or pre-existing substance use disorders. The risk of mortality is present at all doses and increases as the dose increases. Simultaneous consumption of other psychoactive medications may increase overdose risk. The best method to prevent overdose in these patients is to decrease the amount of opioid consumed to the minimal effective dose, or to wean patients from opioids entirely. However, a significant proportion of opioid-dependent patients will struggle with weaning, and it is this group of individuals who are at an increased risk of accidental overdose. Methods to decrease the risk of overdose include improving opioid prescribing to prevent abuse and early recognition of addiction and timely referral to addiction services. Acute illness can increase the effective potency of opioids. Patients and their families need to be made aware of this when initiating therapy and frequently during follow-up. The co-prescribing of naloxone to patients at high risk of overdose is a possible harm-reduction strategy and should be considered for patients consuming opioids or with additional risk because of significant pre-existing illnesses. Naloxone has essentially no pharmacological effect if administered to a patient who has not taken an opioid. Patients can be prescribed naloxone, and family members should be instructed both in the assessment of suspected opioid overdose and in the administration of naloxone. The usual route in overdose is i.v., but the intra-nasal route has proved to be effective in a community setting, where it will most likely be administered by non-medically trained individuals.17Barton E.D. Colwell C.B. Wolfe T. Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting.J Emerg Med. 2005; 29: 265-271Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Chronic opioid therapy has proved beneficial to certain groups of patients. Use of tapentadol (mu-opioid agonist and noradrenaline re-uptake inhibitor) has been shown to be associated with a clinically significant reduction in pain intensity over a 3-week period in patients with chronic, painful diabetic neuropathy (100–250 mg twice per day). This reduction in pain intensity was sustained for a further 9 weeks.18Vinik A.I. Shapiro D.Y. Rauschkolb C. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy.Diabetes Care. 2014; 37: 2302-2309Crossref PubMed Scopus (86) Google Scholar The most common adverse events were gastrointestinal, which caused 10% of patients to discontinue the medication. Use of opioids including tapentadol in patients older than 75 yr with back pain and knee pain caused by osteoarthritis has also been studied.19Biondi D.M. Xiang J. Etropolski M. Tolerability and efficacy of tapentadol extended release in elderly patients ≥75 years of age with chronic osteoarthritis knee or low back pain.J Opioid Management. 2015; 11: 393-403Crossref PubMed Scopus (28) Google Scholar Differences in improvements in pain intensity are not statistically significant, but tapentadol appears to have a better gastrointestinal adverse effect profile.20Afilalo M. Morlion B. Efficacy of tapentadol ER for managing moderate to severe chronic pain.Pain Physician. 2013; 16: 27-40PubMed Google Scholar Psychological techniques and interventional procedures are limited in these patients, and so medications are mainstay of treatment. A reduction in treatment-associated adverse effects is desirable, but it is unknown whether stopping opioids reverses these. Despite the lack of evidence for opioids in chronic non-cancer pain, prescribing has increased substantially over the past 20 yr. Both the clinician and the patient have responsibilities regarding the safe prescribing and use of opioids for chronic non-cancer pain. The challenges facing clinicians are to prevent further increases in rates of opioid prescribing and, after a successful opioid trial, to ensure those who benefit are prescribed opioids by an appropriately trained professional.