- Email: [email protected]
Opioids in the management of persistent non-cancer pain
Pain
Opioids in the management of persistent non-cancer pain
prevalent of musculoskeletal conditions. It affects up to 33% of the population and leads to massive loss of productivity. Treatment of persistent pain Specialist pain management services provide effective care at a low cost when compared with many other secondary care services. Most pain management occurs in primary care, so communitybased staff and the public need education and information about available pain management strategies. Guidance about the use of strong opioids is especially important as more patients ask for this therapy. The British Pain Society has published recommendations for healthcare professionals and advice for patients about the use of opioids for persistent non-cancer pain and also about pain and substance misuse.3–6 Multimodal therapy is more effective than monotherapy, and pharmacological therapies should form only part of an integrated management plan to improve physical and social function. Problem drug use is an issue that cannot be ignored in the context of the current ubiquitous opioid prescribing for conditions that are not life-limiting.
Karen H Simpson Eoin McDonnell
Abstract Opioids can be a useful part of an integrated pain management strategy for selected patients with persistent non-cancer pain, but their use must be carefully considered and appropriate. Recommendations for clinical practice have been produced by several countries, and key themes emerge which encourage responsible prescribing and monitoring. Areas for future research include finding drugs or drug combinations that give maximum efficacy and minimize side effects, such as opioid-induced bowel dysfunction, tolerance and dependence. A balance needs to be achieved, where opioids are not withheld because of fears about problem drugs use, but indiscriminate prescribing is not encouraged.
Use of strong opioids for persistent non-cancer pain A better understanding of pain mechanisms and opioid efficacy has expanded indications for strong opioids for non-cancer pain, including neuropathic pain. There is good evidence for increased opioid consumption in England, which is available from Department of Health prescribing data; the number of prescription opioids dispensed via community pharmacies increased from around 5.5 million in 1998 to almost 9.5 million in 2004. Current opinion is that, in selected patients, strong opioids can provide analgesia and perhaps improve quality of life, without leading to escalating doses and/or problem drug use. The propensity of opioids to cause addiction accompanies their analgesic and mood-altering effects. There are still many unanswered questions about efficacy and risks with prolonged opioid use; there are very few adequate randomized controlled trials of opioid therapy on which to base practice.7 Therefore, prescribers must exercise judgement and care when considering this treatment. Patients with persistent pain can often have poorly defined conditions, difficult behavioural problems and unsupportive social situations. The long-term consequences of opioids in this setting are still poorly understood. Pain management must be the primary goal when opioids are used; not anxio lysis or sedation. All healthcare professionals involved in managing persistent pain should address behaviours and coping styles that increase disability and dependence. Secondary improvements in sleep, physical, psychological and social function may occur with opioid analgesia; however, there is little good-quality supporting evidence for these secondary improvements as yet. Individuals vary in their response to different opioids and also over time. Changing the route of administration, switching opioids and/or combining them with other analgesic and co-analgesics (e.g. antidepressants and/or anticonvulsants) may optimize efficacy. Side effects with opioids are inevitable, and 80% of patients experience at least one. Side effects should be discussed with patients before treatment and managed prophylactically and promptly.
Keywords hyperalgesia; non-cancer pain; persistent pain; tolerance
Persistent non-cancer pain in the community: the size of the problem Pain that has lasted for 3 months or more is considered as persistent; a recent national ‘snapshot’ poll commissioned by the British Pain Society gave a prevalence of 25%.1 A large European telephone survey showed that 19% of more than 46,000 people surveyed had had pain for at least 6 months: 66% moderate, 34% severe and 46% constant pain; 59% people had pain for 2–15 years.2 Economic effects of persistent pain Persistent pain is often musculoskeletal, and as the population ages, pain will become an even more important problem for society. Musculoskeletal problems account for 1.0–2.9% of the gross national product of many western countries. Osteoarthritis, rheumatoid arthritis, osteoporosis, and low-back pain are the commonest conditions; they are a major burden on individuals, health systems, and social care. Osteoarthritis affects 9.6% of men and 18% of women aged more than 60 years. Increases in life expectancy will make osteoarthritis the fourth leading cause of disability by the year 2020. Rheumatoid arthritis affects 0.3–1.0% of the general population; it is more prevalent among women and in developed countries. Osteoporosis is a major risk factor for fractures. Hip fracture is associated with 20% mortality and 50% permanent loss in function. Low-back pain is the most
Karen H Simpson, FRCA, is Consultant in Pain Medicine at Pain Management Service, Seacroft Hospital, Leeds.
Problems with opioids Pharmacogenetic studies are beginning to reveal why individuals respond differently to different drugs.8 CYP2D6 is an isoenzyme
Eoin McDonnell, FRCA, is Specialist Registrar in Anaesthesia at Pain Management Service, Seacroft Hospital, Leeds.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:2
51
© 2007 Elsevier Ltd. All rights reserved.
Pain
Opioid-induced hyperalgesia is usually characterized by a pain that is more diffuse and often has a wider spatial distribution than the pre-existing pain state.11 It has been reproduced experimentally in humans and animals; thermal hyperalgesia, mechanical allodynia and increased pain behaviour are manifest during opioid withdrawal and also during ongoing administration. The mechanisms and signal transduction pathways that mediate opioid-induced hyperalgesia are similar to those of both opioid tolerance and genesis of neuropathic pain. They include activation of N-methyl-d-aspartate (NMDA) receptors and protein kinase, activation of facilitatory supraspinal loops, up-regulation of spinal dynorphin and apoptosis of spinal dorsal horn neurons. Some studies have shown that the prescription of NMDA antagonists prevent opioid-induced hyperalgesia. Alternatively, patients may require opioid switching, dose reduction or withdrawal.
of the cytochrome P450-system that is expressed as variability in opioid metabolism with subsequent altered drug action. It is estimated that 5–10% of white people metabolize codeine and other CYP2D6 substrates poorly as a result of non-functioning alleles of the CYP2D6 gene; 10–15% are termed intermediate metabolizers and possess weakened enzyme activity. Therefore, about 25% of a white population may fail to achieve optimal analgesia with codeine. Age affects opioid pharmacokinetics via altered body composition and organ function9; the extremes of age are important in this respect. Pharmacodynamics is affected via impaired neurotransmitter/peptide production and changed receptor affinities/populations. Practical recommendations for opioid prescription in elderly patients include meticulous review of indications, initially and at regular intervals. Careful titration should be followed, with conservative choice of dosage when initiating therapy; dosing intervals may need to be lengthened subsequently. Hepato-renal function is another important consideration and some opioids are more susceptible to accumulation with organ dysfunction (e.g. morphine metabolites accumulate in renal failure and methadone handling is affected by altered liver function).
Tolerance is defined as the need for a higher dose of drug to achieve the same clinical effect. It develops to the analgesic and hedonistic effects of opioids, as well as to some of the side effects. Tolerance may occur to the analgesic actions of opioids in the CNS. Human and animal studies have shown the need for escalating opioid doses in the absence of disease progression and the need for higher than usual doses when acute pain occurs in patients receiving chronic opioid treatment. There are distinct mechanisms for tolerance that are related to the anatomical or neuro-anatomical substrate of the different opioid effects. OIBD is predominantly mediated directly via local gut receptors, and is less affected by the type of neuro-adaptations that arise in the CNS. Therefore, there is generally no tolerance to OIBD.
Gastrointestinal effects are the most common side effects of opioids. Opioid-induced bowel dysfunction (OIBD) affects the whole gut. It is often more of a problem for patients than pain. Nausea and emesis is common and usually resolves within days; prophylactic anti-emetics can help. Gastric stasis, satiety, flatulence and constipation persist, and constipation requires prophylactic aperients; stimulant and stool-softening drugs should always be co-prescribed with opioids. OIBD is increasingly recognized as a significant clinical problem. The combination of oral opioids with opioid antagonists that act locally on the gut is a potential future strategy.
Physical dependence is defined as specific withdrawal phenomenon if opioids are stopped abruptly or the dose reduced rapidly; dependence is common in all patients using a stable opioid dosing. Opioid induced up-regulation of the cyclic AMP pathways and noradrenergic mechanisms in the locus coeruleus are involved in the development and expression of physical dependence. Symptoms of opioid withdrawal include arousal and sleeplessness, irritability, psychomotor agitation, diarrhoea, rhinorrhea and pilo-erection. Dependence is not clinically important if opioid withdrawal is tapered and supervised.
Persistent itching is common with opioids and it may be difficult to treat. Oral antihistamines may help but if this problem is intrusive, the opioid should be switched. Itching is difficult to tolerate and often leads to patients choosing to withdraw from opioids. Cognitive effects are common when starting opioids or with dose changes. It may be a particular problem in elderly patients who are prone to falls. The cognitive effects of long-term opioid use are less clear. Stable opioid treatment probably does not adversely affect driving skills.10 However, the healthcare team should remind patients about their social responsibilities and that the patient must not drive whilst impaired. If there is any doubt, then the patient should deal with the Driver and Vehicle Licensing Agency, which is the final arbiter.
Psychological dependence comprises both unpleasant emotional effects (withdrawal anhedonia and dysphoria) and motivational effects (craving). It is probably rare when patients are appropriately prescribed a stable dose of opioid for pain management. Pseudoaddiction was a term coined by Weissman and Haddox to describe reversible opioid-seeking behaviours (drug hoarding, attempts to obtain extra supplies, and requests for early prescription or increased dose) that are seen with under-treated pain. These behaviours are not manifestations of true addiction; they cease when pain is managed properly.
Endocrine and immunological problems occur with long-term opioid treatment. The extent of these problems depends on the opioid used (e.g. buprenorphine causes less immune suppression than morphine). Opioids alter the development of immune cells such as macrophages, natural killer cells, and T and B lymphocytes; however, the clinical significance of this effect is uncertain. Opioid treatment can affect the hypothalamic–pituitary–adrenal axis and the hypothalamic–pituitary–gonadal axis, leading to decreased libido, infertility, amenorrhea, or irregular menses. Patients on long-term opioids should have endocrine monitoring.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:2
Addiction means the compulsive use of opioids to the detriment of the user’s physical and/or psychological health and/or social function.12 It is a chronic neurobiological condition that is produced by repeated exposure to an addictive drug, and is characterized by loss of control over drug use. Neuronal pathways that form the so-called ‘reward circuits’ play a central role in 52
© 2007 Elsevier Ltd. All rights reserved.
Pain
c ompulsive drug-taking and addiction; these are found within mesocorticolimbic dopamine systems, originating in the ventral tegmental area and projecting to the nucleus accumbens, amygdala and prefrontal cortex. Opioids induce dopamine release indirectly by decreasing γ-aminobutyric acid inhibition via μ-opioid receptors in the ventral tegmental area, as well as interacting with opioid receptors in the nucleus accumbens. As addiction develops, the changes that occur in the brain are induced not only by the drug itself, but also by behaviours and circumstances associated with obtaining and using the drug. These effects seem to involve structures involved in memory, conditioning and learning such as the amygdala, hippocampus and cerebral cortex. The use of long-term opioids appropriately prescribed for pain probably only rarely results in addiction. However, there is still considerable uncertainty about the rates of addiction in this group. This uncertainty is related to lack of consensus about definitions and the blurring between problem opioid use and true drug addiction. It is not possible to use screening tools such as questionnaires to predict the likelihood of addiction for individuals prescribed opioids for pain. Several research groups are developing screening instruments that could be used in future to stratify risk, identify deterioration in life measures and record important outcomes in a standardized manner to identify patients who warrant special vigilance and monitoring. If problem drug use occurs in the context of treating persistent pain, then it is important to recognize it quickly and act appropriately. Concern that a patient’s behaviour may indicate addiction should trigger immediate referral to and/or consultation with a specialized drug-addiction unit. Diversion of prescription opioids from their intended recipient does occur. It may be casual (e.g. giving prescribed opioids to friends or relatives with pain) or a deliberate attempt to profit; the latter is a criminal offence. All healthcare professionals have a responsibility to identify and deal with diversion.
a specialized service may be useful (e.g. multidisciplinary pain management service or specialized addiction service). • Healthcare professionals prescribing or maintaining opioid treatment for patients with persistent non-cancer pain should develop, document and agree individualized treatment plans with patients/carers. • Patients should be aware of the limitations and side effects of opioids, and of their own responsibilities when taking opioids. They should be given written information about opioids as a supplement to aid discussions. The concept of a written ‘opioid contract’ has no evidence to support its efficacy in improving patient concordance or reducing problem drug use. • The choice of opioid depends on clinical circumstances, local experience and expertise. There are no good randomized trials that allow clear decisions about opioid selection. Modifiedrelease or transdermal opioids are preferable; immediate-release formulations should be avoided, especially pethidine. Injectable opioids are rarely appropriate in the management of this group of patients. Local recommendations for opioid use should be developed and kept up to date as data emerge. • The primary outcome should be analgesia, but demonstrable improvements in physical, psychological and social function are important secondary aims. • Patients should eventually obtain their medication from a single source, which should be in the community. • Regular assessment must take place in primary and/or secondary care, and should include documented evaluation of pain relief, physical, psychological and social function, sleep, side effects and signs of problem drug use. • Opioid use should be continued only if the benefits outweigh the burdens of treatment. • All healthcare professionals should be alert to the risk of drug diversion and deal with it promptly; this should not impede rational and appropriate opioid prescribing for pain. ◆
Recommendations for opioid prescribing Problems have occurred in several countries when opioid prescribing has become too ubiquitous. Many countries have produced national recommendations about the use of opioids for persistent non-cancer pain. Common themes emerge and are outlined below. • Established relationships are needed between primary and secondary care services in the management of patients prescribed long-term strong opioids for non-cancer pain. • Appropriate specialist assessment of the causes of pain must occur before opioids are initiated. • Opioids should be considered only after the use of other established therapies; effective therapies should be continued in parallel with opioids where appropriate. • A doctor should make the initial decision to use strong opioids for persistent non-cancer pain; extended prescribing roles may mean that other healthcare professionals assist with monitoring and maintaining opioid therapy. • Acute pain teams should not initiate long-term opioids without the support of a multi-professional pain management team and liaison with primary care. • Psychological co-morbidity, social chaos or a history of alcohol/problem drug use does not absolutely preclude the use of opioids. In these circumstances advice from, or referral to,
References 1 Coupe M, Stannard C. Opioids in persistent non-cancer pain. Cont Edu Anaesth Crit Care Pain 2007; 7: 100–3. 2 Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006; 10: 287–333. 3 British Pain Society. Recommendations for the appropriate use of opioids for persistent non-cancer pain and Opioid Medicines for Persistent Pain, 2004. http://www.britishpainsociety.org/book_ opioid_main.pdf (accessed 18 September 2007). 4 British Pain Society. Opioid medicines for persistent pain: information for patients, 2004. http://www.britishpainsociety.org/ book_opioid_patient.pdf (accessed 18 September 2007). 5 British Pain Society. Pain and substance misuse: improving the patient experience, 2007. http://www.britishpainsociety.org/book_ drug_misuse_main.pdf (accessed 18 September 2007). 6 British Pain Society. Pain and problem drug use: information for patients, 2007. http://www.britishpainsociety.org/book_misuse_ patients.pdf (accessed 18 September 2007). 7 Kalso E. Improving opioid effectiveness: from ideas to evidence. Eur J Pain 2005; 9: 131–5.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:2
53
© 2007 Elsevier Ltd. All rights reserved.
Pain
8 Stamer U, Bayerer B, Stuber F. Genetics and variability in opioid response. Eur J Pain 2005; 9: 101–4. 9 Wilder-Smith O. Opioid use in the elderly. Eur J Pain 2005; 9: 137–40. 10 Kress H, Birgit G. Opioid medication and driving ability. Eur J Pain 2005; 9: 141–4. 11 Ruscheweyh R, Sandkuhler J. Opioids and central sensitisation. Induction and reversal of hyperalgesia. Eur J Pain 2005; 9: 149–52.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:2
12 Ballantyne J, La Forge K. Opioid dependence and addiction during opioid treatment of chronic pain. Pain 2007; 129: 235–55.
Further reading Kalso E, Edwards J, Moore R, et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004; 99: 299–307.
54
© 2007 Elsevier Ltd. All rights reserved.
Opioids in the management of persistent non-cancer pain
prevalent of musculoskeletal conditions. It affects up to 33% of the population and leads to massive loss of productivity. Treatment of persistent pain Specialist pain management services provide effective care at a low cost when compared with many other secondary care services. Most pain management occurs in primary care, so communitybased staff and the public need education and information about available pain management strategies. Guidance about the use of strong opioids is especially important as more patients ask for this therapy. The British Pain Society has published recommendations for healthcare professionals and advice for patients about the use of opioids for persistent non-cancer pain and also about pain and substance misuse.3–6 Multimodal therapy is more effective than monotherapy, and pharmacological therapies should form only part of an integrated management plan to improve physical and social function. Problem drug use is an issue that cannot be ignored in the context of the current ubiquitous opioid prescribing for conditions that are not life-limiting.
Karen H Simpson Eoin McDonnell
Abstract Opioids can be a useful part of an integrated pain management strategy for selected patients with persistent non-cancer pain, but their use must be carefully considered and appropriate. Recommendations for clinical practice have been produced by several countries, and key themes emerge which encourage responsible prescribing and monitoring. Areas for future research include finding drugs or drug combinations that give maximum efficacy and minimize side effects, such as opioid-induced bowel dysfunction, tolerance and dependence. A balance needs to be achieved, where opioids are not withheld because of fears about problem drugs use, but indiscriminate prescribing is not encouraged.
Use of strong opioids for persistent non-cancer pain A better understanding of pain mechanisms and opioid efficacy has expanded indications for strong opioids for non-cancer pain, including neuropathic pain. There is good evidence for increased opioid consumption in England, which is available from Department of Health prescribing data; the number of prescription opioids dispensed via community pharmacies increased from around 5.5 million in 1998 to almost 9.5 million in 2004. Current opinion is that, in selected patients, strong opioids can provide analgesia and perhaps improve quality of life, without leading to escalating doses and/or problem drug use. The propensity of opioids to cause addiction accompanies their analgesic and mood-altering effects. There are still many unanswered questions about efficacy and risks with prolonged opioid use; there are very few adequate randomized controlled trials of opioid therapy on which to base practice.7 Therefore, prescribers must exercise judgement and care when considering this treatment. Patients with persistent pain can often have poorly defined conditions, difficult behavioural problems and unsupportive social situations. The long-term consequences of opioids in this setting are still poorly understood. Pain management must be the primary goal when opioids are used; not anxio lysis or sedation. All healthcare professionals involved in managing persistent pain should address behaviours and coping styles that increase disability and dependence. Secondary improvements in sleep, physical, psychological and social function may occur with opioid analgesia; however, there is little good-quality supporting evidence for these secondary improvements as yet. Individuals vary in their response to different opioids and also over time. Changing the route of administration, switching opioids and/or combining them with other analgesic and co-analgesics (e.g. antidepressants and/or anticonvulsants) may optimize efficacy. Side effects with opioids are inevitable, and 80% of patients experience at least one. Side effects should be discussed with patients before treatment and managed prophylactically and promptly.
Keywords hyperalgesia; non-cancer pain; persistent pain; tolerance
Persistent non-cancer pain in the community: the size of the problem Pain that has lasted for 3 months or more is considered as persistent; a recent national ‘snapshot’ poll commissioned by the British Pain Society gave a prevalence of 25%.1 A large European telephone survey showed that 19% of more than 46,000 people surveyed had had pain for at least 6 months: 66% moderate, 34% severe and 46% constant pain; 59% people had pain for 2–15 years.2 Economic effects of persistent pain Persistent pain is often musculoskeletal, and as the population ages, pain will become an even more important problem for society. Musculoskeletal problems account for 1.0–2.9% of the gross national product of many western countries. Osteoarthritis, rheumatoid arthritis, osteoporosis, and low-back pain are the commonest conditions; they are a major burden on individuals, health systems, and social care. Osteoarthritis affects 9.6% of men and 18% of women aged more than 60 years. Increases in life expectancy will make osteoarthritis the fourth leading cause of disability by the year 2020. Rheumatoid arthritis affects 0.3–1.0% of the general population; it is more prevalent among women and in developed countries. Osteoporosis is a major risk factor for fractures. Hip fracture is associated with 20% mortality and 50% permanent loss in function. Low-back pain is the most
Karen H Simpson, FRCA, is Consultant in Pain Medicine at Pain Management Service, Seacroft Hospital, Leeds.
Problems with opioids Pharmacogenetic studies are beginning to reveal why individuals respond differently to different drugs.8 CYP2D6 is an isoenzyme
Eoin McDonnell, FRCA, is Specialist Registrar in Anaesthesia at Pain Management Service, Seacroft Hospital, Leeds.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:2
51
© 2007 Elsevier Ltd. All rights reserved.
Pain
Opioid-induced hyperalgesia is usually characterized by a pain that is more diffuse and often has a wider spatial distribution than the pre-existing pain state.11 It has been reproduced experimentally in humans and animals; thermal hyperalgesia, mechanical allodynia and increased pain behaviour are manifest during opioid withdrawal and also during ongoing administration. The mechanisms and signal transduction pathways that mediate opioid-induced hyperalgesia are similar to those of both opioid tolerance and genesis of neuropathic pain. They include activation of N-methyl-d-aspartate (NMDA) receptors and protein kinase, activation of facilitatory supraspinal loops, up-regulation of spinal dynorphin and apoptosis of spinal dorsal horn neurons. Some studies have shown that the prescription of NMDA antagonists prevent opioid-induced hyperalgesia. Alternatively, patients may require opioid switching, dose reduction or withdrawal.
of the cytochrome P450-system that is expressed as variability in opioid metabolism with subsequent altered drug action. It is estimated that 5–10% of white people metabolize codeine and other CYP2D6 substrates poorly as a result of non-functioning alleles of the CYP2D6 gene; 10–15% are termed intermediate metabolizers and possess weakened enzyme activity. Therefore, about 25% of a white population may fail to achieve optimal analgesia with codeine. Age affects opioid pharmacokinetics via altered body composition and organ function9; the extremes of age are important in this respect. Pharmacodynamics is affected via impaired neurotransmitter/peptide production and changed receptor affinities/populations. Practical recommendations for opioid prescription in elderly patients include meticulous review of indications, initially and at regular intervals. Careful titration should be followed, with conservative choice of dosage when initiating therapy; dosing intervals may need to be lengthened subsequently. Hepato-renal function is another important consideration and some opioids are more susceptible to accumulation with organ dysfunction (e.g. morphine metabolites accumulate in renal failure and methadone handling is affected by altered liver function).
Tolerance is defined as the need for a higher dose of drug to achieve the same clinical effect. It develops to the analgesic and hedonistic effects of opioids, as well as to some of the side effects. Tolerance may occur to the analgesic actions of opioids in the CNS. Human and animal studies have shown the need for escalating opioid doses in the absence of disease progression and the need for higher than usual doses when acute pain occurs in patients receiving chronic opioid treatment. There are distinct mechanisms for tolerance that are related to the anatomical or neuro-anatomical substrate of the different opioid effects. OIBD is predominantly mediated directly via local gut receptors, and is less affected by the type of neuro-adaptations that arise in the CNS. Therefore, there is generally no tolerance to OIBD.
Gastrointestinal effects are the most common side effects of opioids. Opioid-induced bowel dysfunction (OIBD) affects the whole gut. It is often more of a problem for patients than pain. Nausea and emesis is common and usually resolves within days; prophylactic anti-emetics can help. Gastric stasis, satiety, flatulence and constipation persist, and constipation requires prophylactic aperients; stimulant and stool-softening drugs should always be co-prescribed with opioids. OIBD is increasingly recognized as a significant clinical problem. The combination of oral opioids with opioid antagonists that act locally on the gut is a potential future strategy.
Physical dependence is defined as specific withdrawal phenomenon if opioids are stopped abruptly or the dose reduced rapidly; dependence is common in all patients using a stable opioid dosing. Opioid induced up-regulation of the cyclic AMP pathways and noradrenergic mechanisms in the locus coeruleus are involved in the development and expression of physical dependence. Symptoms of opioid withdrawal include arousal and sleeplessness, irritability, psychomotor agitation, diarrhoea, rhinorrhea and pilo-erection. Dependence is not clinically important if opioid withdrawal is tapered and supervised.
Persistent itching is common with opioids and it may be difficult to treat. Oral antihistamines may help but if this problem is intrusive, the opioid should be switched. Itching is difficult to tolerate and often leads to patients choosing to withdraw from opioids. Cognitive effects are common when starting opioids or with dose changes. It may be a particular problem in elderly patients who are prone to falls. The cognitive effects of long-term opioid use are less clear. Stable opioid treatment probably does not adversely affect driving skills.10 However, the healthcare team should remind patients about their social responsibilities and that the patient must not drive whilst impaired. If there is any doubt, then the patient should deal with the Driver and Vehicle Licensing Agency, which is the final arbiter.
Psychological dependence comprises both unpleasant emotional effects (withdrawal anhedonia and dysphoria) and motivational effects (craving). It is probably rare when patients are appropriately prescribed a stable dose of opioid for pain management. Pseudoaddiction was a term coined by Weissman and Haddox to describe reversible opioid-seeking behaviours (drug hoarding, attempts to obtain extra supplies, and requests for early prescription or increased dose) that are seen with under-treated pain. These behaviours are not manifestations of true addiction; they cease when pain is managed properly.
Endocrine and immunological problems occur with long-term opioid treatment. The extent of these problems depends on the opioid used (e.g. buprenorphine causes less immune suppression than morphine). Opioids alter the development of immune cells such as macrophages, natural killer cells, and T and B lymphocytes; however, the clinical significance of this effect is uncertain. Opioid treatment can affect the hypothalamic–pituitary–adrenal axis and the hypothalamic–pituitary–gonadal axis, leading to decreased libido, infertility, amenorrhea, or irregular menses. Patients on long-term opioids should have endocrine monitoring.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:2
Addiction means the compulsive use of opioids to the detriment of the user’s physical and/or psychological health and/or social function.12 It is a chronic neurobiological condition that is produced by repeated exposure to an addictive drug, and is characterized by loss of control over drug use. Neuronal pathways that form the so-called ‘reward circuits’ play a central role in 52
© 2007 Elsevier Ltd. All rights reserved.
Pain
c ompulsive drug-taking and addiction; these are found within mesocorticolimbic dopamine systems, originating in the ventral tegmental area and projecting to the nucleus accumbens, amygdala and prefrontal cortex. Opioids induce dopamine release indirectly by decreasing γ-aminobutyric acid inhibition via μ-opioid receptors in the ventral tegmental area, as well as interacting with opioid receptors in the nucleus accumbens. As addiction develops, the changes that occur in the brain are induced not only by the drug itself, but also by behaviours and circumstances associated with obtaining and using the drug. These effects seem to involve structures involved in memory, conditioning and learning such as the amygdala, hippocampus and cerebral cortex. The use of long-term opioids appropriately prescribed for pain probably only rarely results in addiction. However, there is still considerable uncertainty about the rates of addiction in this group. This uncertainty is related to lack of consensus about definitions and the blurring between problem opioid use and true drug addiction. It is not possible to use screening tools such as questionnaires to predict the likelihood of addiction for individuals prescribed opioids for pain. Several research groups are developing screening instruments that could be used in future to stratify risk, identify deterioration in life measures and record important outcomes in a standardized manner to identify patients who warrant special vigilance and monitoring. If problem drug use occurs in the context of treating persistent pain, then it is important to recognize it quickly and act appropriately. Concern that a patient’s behaviour may indicate addiction should trigger immediate referral to and/or consultation with a specialized drug-addiction unit. Diversion of prescription opioids from their intended recipient does occur. It may be casual (e.g. giving prescribed opioids to friends or relatives with pain) or a deliberate attempt to profit; the latter is a criminal offence. All healthcare professionals have a responsibility to identify and deal with diversion.
a specialized service may be useful (e.g. multidisciplinary pain management service or specialized addiction service). • Healthcare professionals prescribing or maintaining opioid treatment for patients with persistent non-cancer pain should develop, document and agree individualized treatment plans with patients/carers. • Patients should be aware of the limitations and side effects of opioids, and of their own responsibilities when taking opioids. They should be given written information about opioids as a supplement to aid discussions. The concept of a written ‘opioid contract’ has no evidence to support its efficacy in improving patient concordance or reducing problem drug use. • The choice of opioid depends on clinical circumstances, local experience and expertise. There are no good randomized trials that allow clear decisions about opioid selection. Modifiedrelease or transdermal opioids are preferable; immediate-release formulations should be avoided, especially pethidine. Injectable opioids are rarely appropriate in the management of this group of patients. Local recommendations for opioid use should be developed and kept up to date as data emerge. • The primary outcome should be analgesia, but demonstrable improvements in physical, psychological and social function are important secondary aims. • Patients should eventually obtain their medication from a single source, which should be in the community. • Regular assessment must take place in primary and/or secondary care, and should include documented evaluation of pain relief, physical, psychological and social function, sleep, side effects and signs of problem drug use. • Opioid use should be continued only if the benefits outweigh the burdens of treatment. • All healthcare professionals should be alert to the risk of drug diversion and deal with it promptly; this should not impede rational and appropriate opioid prescribing for pain. ◆
Recommendations for opioid prescribing Problems have occurred in several countries when opioid prescribing has become too ubiquitous. Many countries have produced national recommendations about the use of opioids for persistent non-cancer pain. Common themes emerge and are outlined below. • Established relationships are needed between primary and secondary care services in the management of patients prescribed long-term strong opioids for non-cancer pain. • Appropriate specialist assessment of the causes of pain must occur before opioids are initiated. • Opioids should be considered only after the use of other established therapies; effective therapies should be continued in parallel with opioids where appropriate. • A doctor should make the initial decision to use strong opioids for persistent non-cancer pain; extended prescribing roles may mean that other healthcare professionals assist with monitoring and maintaining opioid therapy. • Acute pain teams should not initiate long-term opioids without the support of a multi-professional pain management team and liaison with primary care. • Psychological co-morbidity, social chaos or a history of alcohol/problem drug use does not absolutely preclude the use of opioids. In these circumstances advice from, or referral to,
References 1 Coupe M, Stannard C. Opioids in persistent non-cancer pain. Cont Edu Anaesth Crit Care Pain 2007; 7: 100–3. 2 Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006; 10: 287–333. 3 British Pain Society. Recommendations for the appropriate use of opioids for persistent non-cancer pain and Opioid Medicines for Persistent Pain, 2004. http://www.britishpainsociety.org/book_ opioid_main.pdf (accessed 18 September 2007). 4 British Pain Society. Opioid medicines for persistent pain: information for patients, 2004. http://www.britishpainsociety.org/ book_opioid_patient.pdf (accessed 18 September 2007). 5 British Pain Society. Pain and substance misuse: improving the patient experience, 2007. http://www.britishpainsociety.org/book_ drug_misuse_main.pdf (accessed 18 September 2007). 6 British Pain Society. Pain and problem drug use: information for patients, 2007. http://www.britishpainsociety.org/book_misuse_ patients.pdf (accessed 18 September 2007). 7 Kalso E. Improving opioid effectiveness: from ideas to evidence. Eur J Pain 2005; 9: 131–5.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:2
53
© 2007 Elsevier Ltd. All rights reserved.
Pain
8 Stamer U, Bayerer B, Stuber F. Genetics and variability in opioid response. Eur J Pain 2005; 9: 101–4. 9 Wilder-Smith O. Opioid use in the elderly. Eur J Pain 2005; 9: 137–40. 10 Kress H, Birgit G. Opioid medication and driving ability. Eur J Pain 2005; 9: 141–4. 11 Ruscheweyh R, Sandkuhler J. Opioids and central sensitisation. Induction and reversal of hyperalgesia. Eur J Pain 2005; 9: 149–52.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:2
12 Ballantyne J, La Forge K. Opioid dependence and addiction during opioid treatment of chronic pain. Pain 2007; 129: 235–55.
Further reading Kalso E, Edwards J, Moore R, et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004; 99: 299–307.
54
© 2007 Elsevier Ltd. All rights reserved.