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Acute pain management for opioid dependent patients - Anesthesia 2006

Acute pain management for opioid dependent patients - Anesthesia 2006

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  • 1. REVIEW ARTICLE Acute pain management for opioid dependent patients V. Mehta1 and R. M. Langford2 1 Clinical Lecturer ⁄ Specialist Registrar, Boyle Department of Anaesthesia 2 Director, Anaesthetic Laboratory, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK Summary Patients requiring acute pain management may be opioid dependent as a result of either recreational or therapeutic opioid use, including those in opioid addiction programmes. Pain in these patients is often under-estimated and under-treated. In addiction, drug-seeking behaviour differentiates it from simple dependence. With few randomised controlled trials, current evidence predominantly consists of guidelines based on case reports, retrospective studies and expert opinion. Consensus recom- mendations include maintaining regular provision of the patient’s pre-existing opioid requirement, with additional analgesia, ideally multimodal, in appropriate combinations of short-acting opioid (as required), local anaesthesia, and adjuvant anti-inflammatory analgesics and paracetamol. Patient controlled analgesia with higher bolus doses and shorter lock-out intervals is a recommended stra- tegy. Transdermal opioid patches and implantable pumps will continue to deliver opioid, to which non-opioid and short-acting opioids may be added. Re-exposure to opioid is ideally avoided in previously addicted patients, but if not feasible, opioid therapy should be prescribed. ........................................................................................................ Correspondence to: Prof. Richard M. Langford E-mail: r.m.langford@qmul.ac.uk Accepted: 7 October 2005 This article examines the additional and potentially challenging issues in the management of acute pain in patients who have been exposed to long-term opioids, whether of therapeutic or recreational origin, with or without known opioid dependence. This population is increasing and includes patients with cancer and non- cancer pain patients. The use of strong opioids has been encouraged in non-cancer pain patients in response to greater awareness of the prevalence of their inadequately treated pain, and has been facilitated by the introduction of convenient oral sustained release and transdermal ‘patch’ methods of administration. Their use has been steadily gaining acceptance as an appropriate and effective method of pain management in some cases of persistent non-cancer pain in both Europe and the USA [1–3]. Guidelines for the use of opioids have recently been published by the British Pain Society in consensus with the Royal Colleges of Anaesthetists, General Practitioners and Psychiatrists. Patients on long-term opioid therapy are more likely to require surgery and higher doses of opioids postoperatively [4, 5]. It has been roughly estimated from market surveillance data that there were around 2.5 million strong opioid prescriptions in the primary care setting in 2004 for both cancer and non- cancer pain (excluding prescribing for addicts in opioid maintenance programmes). Definitions Understanding the nature of the patient’s condition, and hence the terminology applied in this area of medicine are important in deciding how best to treat the pain. Addiction, physical dependence and tolerance have been defined by a Joint Consensus Statement of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. Addiction is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterised by behaviour that includes one or more of the following: impaired control over drug use, compul- sive use, continued use despite harm, and craving. Physical dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level, and ⁄ or administration of an antagonist. Physical dependence is a neuropharmaco- logical phenomenon as a result of neuroadaptation and Anaesthesia, 2006, 61, pages 269–276 doi:10.1111/j.1365-2044.2005.04503.x ..................................................................................................................................................................................................................... Ó 2006 Blackwell Publishing Ltd 269
  • 2. neuroplasticity, while addiction is both a neurophar- macological and a behavioural phenomenon [6]. It is important to recognise that though physical dependence and addiction might be very similar, not all physically dependent individuals are addicts. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a decrease of one or more of the drug’s effects over time. In the context of opioids, it is important to remember that there is an evidence of tolerance to both the analgesic and the side- effect profile. Prevalence of substance abuse A report from the UK focal point to European monit- oring centre for drugs and drug addiction (EMCDDA 2002) estimates that 34% of those aged 16–59 years had at some time abused drugs or solvents, and this figure rises to around a half of the population in the age group 16–29 years. The drugs included cannabis, hallucinogens, amphetamines, cocaine, ecstasy and opioids. However, use of opioids (such as heroin or methadone) has a relative low lifetime prevalence (overall 1.1%). Among males, 0.9% of those aged 16–24 reported opioid use as compared to 0.5% for females [7, 8]. In recent years, the UK has accounted for the greatest proportion of heroin seized in Western Europe, reaching a peak of 3930 kg in 2001, before dropping to 2730 kg in 2002. A recent comparison made of different methods of estimating the number of ‘problematic opioid users’ in Great Britain, arrived at the figure of about 202 000 [9]. Prevalence of dependence in chronic pain patients Though the actual prevalence of opioid dependence in patients having chronic pain is hard to identify, Kouya- nou et al. reported a substantial percentage of those who are attending chronic pain clinics. Of 125 chronic pain clinic patients, 69.6% were on opioid analgesics (inclu- ding codeine), and 12% were diagnosed to have psycho- active substance abuse or dependence disorder using DSM-III-R criteria [10]. Other studies have estimated 3–16% rates of addiction in patients who complain of chronic pain [11, 12], albeit in diverse pathological conditions, and using different definitions of addiction. Pathophysiology Cellular adaptations Chronic opioid exposure leads to widespread adaptations at the cellular and the synaptic level, and is responsible for the phenomenon of tolerance and dependence. Doses of morphine which are several times those used in opioid naı¨ve patients have been reported to produce only mild physiologic effects in some opioid addicts [13] and chronic pain patients [14]. The G-protein linked opioid receptors activate and regulate multiple second messenger pathways associated with effector coupling, receptor trafficking, and nuclear signalling [15]. The coupling of these receptors to G-proteins leads to inhibition of adenyl cyclase, activation of potassium conductance, inhibition of calcium con- ductance, activation of protein kinase C, release of calcium from internal stores and inhibition of the release of other transmitters, which may include GABA [15]. Tolerance is thought to involve receptor desensi- tisation, internalisation and down-regulation, whereas dependence and withdrawal are primarily due to opioid receptor counter-adaptation. Desensitisation, internalisation and down-regulation Tolerance to opioids has been attributed to a decrease in the density of O-opioid receptors on the cell membrane and to desensitisation [16, 17]. The most popular hypothesis for the mechanism is that the receptors are phosphorylated (by G-protein coupled receptor kinases), resulting in uncoupling from their G-proteins, and endocytosis or ‘internalisation’ [16, 18]. It has been hypothesised that differences between opioids in addiction potential or benefit in treatment programmes may relate to their differential propensity to induce internalisation [15, 19, 20]. Counter-adaptations In chronic opioid treatment, the counter-adaptive pro- cesses are believed to involve up-regulation of adenyl cyclase, with consequent increases in the release of transmitters such as GABA and glutamate [21, 22]. It has further been suggested that cAMP changes mediate an increase in cation conductance, causing increased excitability in the peri-aqueductal grey and dorsal raphe areas [23, 24]. Acute pain management As it is common to under-estimate and under-treat pain in opioid dependent patients, it is important to identify the goals in their acute pain management (Table 1). Acute pain management in opioid dependent patients is a complex issue. There has been a tendency to use opioids sparingly, resulting in both poor pain management and withdrawal phenomena [25]. Patients may well have had negative experiences with the health and the social system, and may react with a degree of suspicion, mistrust or even hostility. It is important to gain the trust of the V. Mehta and R. M. Langford Æ Pain management for opioid dependent patients Anaesthesia, 2006, 61, pages 269–276 ...................................................................................................................................................................................................................... 270 Ó 2006 Blackwell Publishing Ltd
  • 3. patient, by both the patient and staff dealing with the issues openly and honestly. The patient needs to be reassured that their drug history and dependence will not be an obstacle to the relief of their pain [26]. During assessment, care should be exercised to maintain privacy and confidentiality [27]. History taking, though not infallible, still forms the backbone of risk assessment. Opioid dependent patients These patients may be dependent as a result of long-term pain therapy or opioid abuse. With few randomised controlled trials, the evidence predominantly consists of guidelines drawn up from case reports, retrospective studies and opinion from expertise in the field. However, the consensus is that the pre-existing opioid usage should be continued as a baseline, and additional analgesia provided, as required. There are inherent difficulties in estimating the correct dosage of opioids being used in patients who obtain drugs by illicit means. The inevitable variability of illicitly manufactured drugs is a problem in estimating equivalent opioid dosage, and on occasion this may be compounded by a lack of frankness about the types and doses of drugs taken. Generally, however, it is feasible to gain the patient’s trust and co-operation by reassurance that confidentiality will be maintained and that the goal is to achieve adequate pain control. Although, opioid usage for acute pain management in opioid dependent patients has been controversial, it is now generally accepted that opioids may be used safely and effectively in opioid dependent patients. Since tolerance to the side-effect profile develops more rapidly than the analgesic effects, they may be safely titrated to high doses to achieve adequate analgesia [26]. It is important to complement the therapy with simple analgesics, local and regional anaesthesia and non-phar- macological manoeuvres where possible. General treatment guidelines Local anaesthetic techniques: If feasible, local anaesthetic techniques should be used as sole or adjunct pain relief, as it has been shown to be particularly advantageous in opioid dependent patients, potentially obviating the need for additional opioids [28, 29]. However, disadvantages may include lack of patient compliance [30], infection risk from needle-stick injuries, and a need for reduction in the dose of local anaesthetic if there is either pre-existing hepatic dysfunction or significant hypoalbuminaemia [31]. NSAIDS, paracetamol and adjuvant drugs and techniques: Multimodal analgesia [32] with paracetamol, NSAIDs and adjuvant drugs remains the backbone of pain management in the same way as it is in patients without any drug dependence. Once the underlying opioid requirement has been met, the patients should be treated within the model of the analgesic ladder to ensure adequate pain relief. NSAIDs and selective COX-2 antagonists, being devoid of central depressant or mood altering effects, are ideal alone or in combination in this group of patients [26]. However, it is important to remember that they have a ceiling effect, and care has to be taken regarding renal, hepatic and gastro-intestinal side-effects. Ketamine: Low dose ketamine has been successfully used to enhance morphine induced analgesia [33]. Apart from its antagonist action on NMDA receptors, an antagonist-agonist action on O-opioid and agonist action on noradrenergic a2 and 5-HT receptor has been proposed [34]. Successful acute pain treatment in an opioid dependent patient has been reported with mor- phine plus adjuvant ketamine [35]. Physical interventions including thermal modalities such as heat ⁄ cold application, manual therapies like massage and manipulation may be successful as in the general population. Opioid medications Dosage and timing: Opioids should be prescribed on a regular rather than prn, as needed, basis. For background maintenance, the average baseline opioid dosage should be determined and either the same drug or an alternative opioid should be given in equi-analgesic dosage [26]. Opioids should be given in sufficient amounts to achieve the desired analgesic effect, or until limited by any side- effects such as sedation and respiratory depression [27]. It is also recommended to provide multiple opioid therapy, with for example parenteral increments of morphine or fentanyl titrated in addition to the baseline opioid. Opioid rotation: Opioid rotation, with switching to a different opioid, has been recommended if adequate pain control cannot be achieved by increasing the opioid dose. Side-effects can prevent continuing dose escalation in some cases. Much of the work on opioid rotation comes from palliative care requiring large doses of opioid analgesics to achieve satisfactory pain control [36–39]. It Table 1 Goals of acute pain management in opioid dependent patients. 1 Identification of the populations at risk: patients on long-term opioid therapy for various chronic pain situations (musculoskeletal, neuropathic, sickle cell disease, HIV related disease and palliative care), drug abusers, recovering addicts in opioid maintenance programmes 2. Prevention of withdrawal symptoms and complications 3 Symptomatic treatment of psychological affective disorders such as anxiety 4 Effective analgesic treatment in the acute phase 5 Rehabilitation to an acceptable and suitable maintenance opioid therapy Anaesthesia, 2006, 61, pages 269–276 V. Mehta and R. M. Langford Æ Pain management for opioid dependent patients ...................................................................................................................................................................................................................... Ó 2006 Blackwell Publishing Ltd 271
  • 4. has been hypothesised that incomplete cross-tolerance enables the substitute opioid to achieve improved pain control at lower dosage, with fewer adverse effects, as a result of reduced levels of both the parent compound and any accumulation of toxic metabolites [36]. Such variable degrees of cross-tolerance require a cautious approach when switching, and it is recommen- ded that dosing is started at half to two thirds of the dosage, estimated from equipotency tables. With wide individual differences, the published ‘equi-analgesic dose tables’ should only be used to provide rough guidelines. Furthermore, they may also differ according to the direction of switch, with important clinical implications [37]. It has been further suggested that complete switch to short-acting opioid medication may result in intermittent withdrawal episodes between doses in dependent patients. Therefore they should be prescribed either with long- acting opioids, or by continuous infusion [40]. There is a need for good quality studies of opioid switching, in both the chronic and acute pain settings. Methadone has been used successfully in substitution for morphine when the latter failed to provide adequate analgesia in an opioid dependent patient [41]. It has been conjectured that methadone and morphine by virtue of their different structures act differently on O receptor subtypes, so as to allow methadone to act on receptors to which tolerance has not been developed. Actions medi- ated by b-adrenergic and NMDA receptors may also contribute to methadone’s analgesic properties [42]. Once the equi-analgesic dose has been calculated, the initial dose of the new drug is given at one-half to two-thirds of the calculated dose to avoid the potential consequences of opioid specific tolerance and inter-individual variability [26]. A correlation between the prerotation morphine dosage and the conversion dose ratio with methadone has been reported [38]. Lawlor et al. conducted a retrospec- tive analysis of consecutive rotations involving morphine to methadone and reported a three-fold higher median dose ratio (16.84) for those patients receiving > 1165 mg per day of morphine than the median dose ratio (5.42) for patients who were receiving morphine < 1165 mg per day. In clinical practice, using standard equi-analgesic table guidelines in patients on a high dose of morphine could result in methadone toxicity. The same authors using a similar retrospective analysis of morphine and hydromorphone rotation report the dose ratio to be a function of the direction of the opioid switch [39]. Their data indicate that hydromorphone is five times more potent than morphine when given second (rotating morphine to hydromorphone), but only 3.7 times more potent when given first (rotating hydromorphone to morphine). Although these data come from palliative care studies, there may well be important clinical lessons for switching of high opioid doses in chronic non-cancer pain patients. In the case of using the partial agonist buprenorphine for substitution, there is the theoretical possibility of precipitating withdrawal. Indeed, this has been demon- strated in animal studies, but in opioid dependent patients the problem appears to be limited to substitution of buprenorphine over methadone [43]. Routes of administration: In the acute pain setting, parenteral administration will often be required for convenience and rapid titration. Patient controlled analgesia (PCA), though controversial [27], has been used successfully for treatment in patients who are opioid dependent [26]. The strengths and weaknesses of PCA in this patient population are summarised in Table 2, together with treatment guidance. The bolus dose required may be highly variable for the individual, and could need repeated assessment and readjustments. Larger bolus doses with a brief lock out period are recommended to ensure adequate analgesia. Repeated high dosing might be erroneously regarded as drug seeking behaviour by other medical and nursing staff, and hence it is essential that senior staff determine the PCA settings [26]. The ‘wrist-watch’ PCA device design may be consid- ered inferior to the electronic pump type of PCA, as it has a fixed lock-out time, and the opioid reservoir is insecure. Table 2 Advantages and disadvantages of patient controlled analgesia.Advantages 1 Easy to use and accepted standard practice in the acute pain setting 2 Promotes maintenance of a stable blood opioid concentration, providing uniform pain relief at a lower total dose [52], thereby avoiding: sedation at high peak levels pain, anxiety and drug craving at trough levels [26] 3 Patients appreciate being ‘in control’, and maybe reduced likelihood of confrontational behaviour Disadvantages 1 Potentially difficult to optimise dose size and lock out time due to wide between patient variability 2 Patients might use PCA dose for psychological effects rather than analgesic purpose [27] 3 PCA device needs to be tamper-proof, as the patients are aware of the opioid source [53] 4 Frequent need of opioid might be perceived as drug craving by health care professionals V. Mehta and R. M. Langford Æ Pain management for opioid dependent patients Anaesthesia, 2006, 61, pages 269–276 ...................................................................................................................................................................................................................... 272 Ó 2006 Blackwell Publishing Ltd
  • 5. If available, the recently developed fentanyl PCA patch may be considered as an alternative route, although in this setting it has the major disadvantage of not being re- programmable to different bolus doses or lock-out times. Oral transmucosal fentanyl has been successfully used in the management of breakthrough pain in patients on chronic opioid pharmacotherapy [44, 45]. Transdermal or implantable pump opioid therapy: Implan- table pumps are intended for very long-term therapy. They are surgically placed below the skin and can deliver drug continuously subcutaneously, intravenously or in- trathecally for up to 3 months between refills. They consist of a reservoir which is refilled by locating the rubber diaphragm access port of the device. In addition to the general implications of chronic opioid therapy for acute pain management, one needs to be aware that such a patient will continue to receive the opioid from the device. However, the fixed rate pumps can be emptied, and the contents then replaced either with saline, a different opioid concentration, or another opioid. In the case of an opioid transdermal patch, although it can easily be removed, clinically relevant drug doses continue to be absorbed from the skin layers for up to 12 h. It may be reasonable to leave the patch in place to provide the patient’s pre-existing opioid requirement, and then prescribe additional short-acting analgesics for the period of acute pain [46]. It has been suggested that patients on transdermal buprenorphine therapy may ideally be managed with additional immediate release (sublingual) buprenorphine to avoid the risk of agonist–partial agonist interaction and undesirable effects [47]. With increasing use of trans- dermal buprenorphine, there is a need for studies of acute pain management in this group of patients. Table 3 Guidelines for acute pain management in patients on long-term opioids. Patient on high dose opioids Patients on methadone maintenance • Continue prescribed methadone • Poly-opoioid therapy for acute burden Patients on transdermal or implantable pumps • Continue patch or pump • Additional short acting analgesia for acute pain. • Avoid risk of any agonist- antagonist reaction Preoperative administration of maintenance opioid Multimodal analgesia with local anaesthesia infiltration, nerve blocks, paracetamol, NSAIDs and adjuvant drugs Post operative daily maintenance : approximate dose calculation* Oral morphine : iv morphine (3 mg: 1 mg) Oral oxycodone : iv morphine (1-1.5 mg: 1 mg) Transdermal fentanyl : oral morphine (100 µg.h–1: 200 mg.day–1) Transdermal buprenorphine: oral morphine (35 µg.h–1: 30 mg.day–1) Short acting opioid PCA – large bolus dose with shorter lock out interval In poorly controlled pain or with opioid related unacceptable side effects – consider opioid rotation with either Methadone or Oxycodone or Fentanyl or Hydromorphone – acute cancer pain only *It is advisable to reduce the calculated dose due to incomplete cross-tolerance among different opioid groups. Anaesthesia, 2006, 61, pages 269–276 V. Mehta and R. M. Langford Æ Pain management for opioid dependent patients ...................................................................................................................................................................................................................... Ó 2006 Blackwell Publishing Ltd 273
  • 6. Patients on methadone maintenance for opioid addiction: Stabilised patients being managed in a methadone main- tenance programme for opioid addiction present a significant challenge in acute pain management. It has been proposed that cellular and molecular changes induced by chronic opioid usage result in the endogenous opioid system response to acute pain to be less effective. Clinically, the patient is less able to tolerate pain, with consequently higher reported pain scores [48]. Indeed, it has been suggested that apart from analgesic tolerance, it is intolerance to pain that results in increased opioid requirement in methadone maintained patients. A group of opioid dependent patients who were maintained on methadone have been shown to have a significantly lower tolerance to a cold pressor stimulus than matched non- dependent control subjects [49]. In surgical patients undergoing liver transplantation, increased intra- and postoperative analgesic requirements were found in methadone maintained patients compared to the matched control group [50]. General guidelines for this group of patients include continuation of the prescribed methadone dosage (orally, intramuscularly or subcutaneously) and, in addition, providing a rapid onset opioid analgesic for the increased ‘burden’ of acute pain control (Table 3). Experimental data suggest that methadone patients exhibit cross-toler- ance to the antinociceptive effects of morphine and hence conventional doses are likely to be ineffective in managing acute pain episodes. The long and somewhat unpredictable duration of action ⁄ half-life of methadone render it inappropriate for acute pain management, further supporting the rationale of prescribing short- acting opioid agonists in conjunction with background methadone maintenance. Polyopioid therapy is recom- mended as the adjuvant opioid can be easily tapered off once the acute pain has subsided. Co-administration of partial agonists such as pentazocine and buprenorphine have resulted in opioid withdrawal phenomena, and should be avoided [51]. Conclusion Acute pain management in opioid dependent patients remains a challenging and complex problem and is becoming more common. In the acute pain setting, such patients require maintenance of their daily opioid requirement plus multimodal analgesia, including local anaesthesia, anti-inflammatory drugs and additional short- acting opioids, as required. Adjuvant techniques including physical treatment approaches have been used in con- junction with pharmacological methods as a part of a multimodal approach. Opioid rotation may be a useful option; however, it is important to recognise that equivalence conversion tables are only indicative. 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