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Acute pain management in the opioid-tolerant patient
Practice Points
Stephan A Schug* Opioid-tolerant patients are using opioids long term to treat cancer and/or chronic pain, or are addicted
to opioids they use illicitly or in drug substitution programs. Opioid-tolerant patients experience more severe pain for longer periods of time and require higher
opioid doses in acute pain situations. Due to the complexity of their situation, including psychiatric and medical comorbidities, these patients
require a coordinated multidisciplinary approach with good communication between team members and the patient. Principles of acute pain treatment in opioid-tolerant patients are provision of good analgesia, prevention
of withdrawal and discharge planning. Provision of good analgesia relies on a multimodal approach based on the use of nonopioid analgesics
(paracetamol/acetaminophen, NSAIDs or COX-2 inhibitors), antihyperalgesics (ketamine, gabapentin or pregabalin) and regional analgesia with titrated opioid use. Prevention of withdrawal is best achieved by continuation of preadmission opioid regimens, including
substitution with methadone and buprenorphine. Discharge planning requires liaison with all healthcare providers involved to provide appropriate
analgesia and continue opioid supply, while preventing diversion and accidental or intentional overdose.
SUMMARY Opioid use is increasing worldwide leading to an increasing number of opioid-tolerant patients requiring acute pain management after surgery, trauma and acute diseases. Provision of analgesia in opioid-tolerant patients is complex due to the pharmacological effects of long-term opioid exposure, but also due to pre-existing pain states, comorbidities and psychosocial issues. Acute pain management in these patients is governed by the principles of provision of good analgesia, avoidance of withdrawal and organized discharge. Pain relief needs to be achieved by the use of multimodal analgesia, including regional anesthetic techniques and, if needed, opioids in increased doses. Withdrawal is best *Pharmacology & Anaesthesiology Unit, School of Medicine & Pharmacology, University of Western Australia, Australia and Department of Pain Medicine, Royal Perth Hospital, UWA Anaesthesia, Level 2, MRF Building G Block, Royal Perth Hospital, GPO Box X2213, Perth WA 6847, Australia Tel.: +61 8 9224 0201; Fax: +61 8 9224 0279; [email protected]
10.2217/PMT.12.57 © 2012 Future Medicine Ltd
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The number of opioid-tolerant patients who need treatment for acute pain is increasing worldwide. This is due to a combination of the following factors: worldwide opioid consumption is increasing significantly [1]; more cancer pain patients survive longer and get better analgesia; opioid use in chronic pain of nonmalignant origin is increasing significantly [2]; and there is a large group of patients who are either abusing opioids or are on substitution opioids for previous opioid abuse. In addition, patients who are abusing opioids or are on substitution programs have an increased risk of trauma and significant comorbidities requiring surgical intervention, which leads to a further increase in the numbers of such patients requiring acute pain management [3]. In view of the pharmacological considerations and, often even more so, the accompanying psychosocial issues, these patients are usually complex and require significant, often multidisciplinary, input to achieve good outcomes [4]. This situation is further complicated because the scientific evidence for managing these patients is poor [5]. Therefore, a lot of the treatment is more experience than evidence based and the anecdotal evidence might be flawed or unsupported. It is not surprising that a recent review on this topic was published in the ‘Art & Science’ section of a journal [6]. However, there is general agreement that patients who are opioid tolerant require provision of excellent analgesia and appropriate measures to prevent withdrawal, as they are often already affected by anxiety, depression and other psychiatric comorbidities [7]. Not relieving their pain appropriately can result in a dramatic increase of such problems in the face of acute injury or postsurgery, when patients often have difficulty coping anyway. The stigma of drug abuse and the perception of inappropriate opioid use in many opioid-tolerant patients govern the thinking of medical and nursing staff [4]. Often significant prejudices are obvious and lead to inappropriate comments and neglect of pain relief required [8]. In addition, there are often large deficits in education and training of personnel involved in these cases. Both the prejudice and the lack of education and training carry the risk of mistaking reports of pain as seeking opioids or having withdrawal symptoms. Furthermore, there is the risk of not
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recognizing withdrawal symptoms and intoxication and not separating these from other pathologies. Last, but not least, it is totally inappropriate, but attempts are sometimes made to treat addiction in the acute period after trauma or surgery, and such attempts can lead to further problems. The correct approach to the acute pain management of the opioid-tolerant patient requires knowledge, experience and empathy, but also clear directions to avoid major rifts among members of the treating team and additional behavioral problems [7]. The following review attempts to summarize the current, albeit limited, know ledge on the management of acute pain in this diverse but often difficult group of patients. Definitions This review will deal with the issues of acute pain management in opioid-tolerant patients. Acute pain management can become necessary in the postoperative period, after trauma and in patients with acute diseases causing pain. Opioid-tolerant patients are patients who have been exposed to opioids for long periods of time; most data suggest that continuous exposure to opioids for 10–14 days results in the development of tolerance [9]. Tolerance is only one of the phenomena observed in these patients; there are a number of other issues that complicate their management. These include physical dependence, addiction, pseudoaddiction, opioid-induced hyperalgesia and, as a consequence of these, withdrawal symptoms and craving. Definitions of these and other relevant terms are provided in Table 1. Patients can be opioid tolerant for a variety of reasons; a list can be found in Box 1. Size of the problem As mentioned previously, licit opioid consumption is increasing rapidly. This development has been primarily led by developments in the USA; here 4.6% of the world population consume 80% of the licit global opioid supply [10]. Reasons are, to some extent, the more aggressive and longerlasting treatment of cancer survivors, but to a much larger extent, the increasing preparedness of the medical community to treat chronic pain of nonmalignant origin with opioids [11]. This trend may be justified for defined nociceptive (e.g.,
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Table 1. Definitions of relevant terms. Term
Definition
Tolerance
A decrease in the effectiveness of a drug over time with prolonged intake. This leads to an increase in requirements for the drug to achieve the same effect or decrease in effectiveness with maintaining a stable drug dose. Tolerance to many drugs can develop and can be based on pharmacokinetic and pharmacodynamic factors. Tolerance can develop to some, but not all, effects of a drug, and can develop at different rates A physiological phenomenon with prolonged intake of a drug that leads to withdrawal symptoms when the drug is abruptly discontinued, reduced in dose or antagonized. This is a pharmacological and not a psychological mechanism and can develop both to drugs with a psychotropic effect (e.g., opioids) as well as to other drugs (e.g., β blockers) Addiction is commonly defined as a disease characterized by aberrant drug seeking and maladaptive drug taking behaviors, and loss of control over drug use despite obvious physical, social and psychological harm. Addiction is not necessarily connected to the pharmacological phenomena of tolerance and physical dependence, but can be reinforced by these. It is important to note that tolerance and physical dependence are predictable effects of a given drug, while addiction is influenced not only by the addiction liability of a specific drug, but also by psychological, social, environmental and genetic factors in the user An iatrogenic syndrome of abnormal behavior developing as a direct consequence of inadequate pain management. This is often the direct result of inadequately prescribed or inadequately provided analgesia, but misread as drug seeking and presenting with overarching pain behavior to obtain more opioids Symptoms of varying severity after complete or incomplete withdrawal of a psychotropic substance that had been previously used long term. Withdrawal symptoms to opioids include agitation, restlessness, anxiety, dysphoria and hyperalgesia, in particular with abdominal pain, hypertension, tachycardia, increased respiratory drive, diarrhea, muscle spasms, increased sensitivity to cold, gooseflesh and mydriasis [40]. They reflect the increased neuronal excitation after removal of a CNS-dampening substance Strong desire to obtain a psychotropic substance Opioid use may paradoxically lead to an increased sensitivity to pain. This phenomenon has been described with short- and long-term use of various opioids, primarily in animal and volunteer experiments. The relevance for the clinical setting is currently heavily debated
Physical dependence Addiction
Pseudoaddiction
Withdrawal symptoms
Craving Opioid-induced hyperalgesia
Adapted from [5,21,25,45,49–51].
osteoarthritis) and neuropathic (e.g., postherpetic neuralgia) pain states, but is not necessarily supported by evidence for the management of dysfunctional pain conditions, such as fibromyalgia, nonspecific chronic low back pain and interstitial cystitis [12]. Nevertheless, patients with these conditions are prescribed increasing doses of opioids long term with significant implications, not only with regard to the development of tolerance, but also potentially opioid-induced hyperalgesia. Other consequences are the increasing problems with diversion of licitly prescribed opioids into the illicit market [13]. Prescription opioids have not only become the most common drugs abused in many countries, but are also contributing to an increasing rate of prescription drugrelated overdoses with significant mortality [14]. It is hard to describe the situation better than a paper in The New England Journal of Medicine titled “A flood of opioids, a rising tide of death” [2]. Morphine consumption worldwide increased from 7 tons in 1989 to 42 tons in 2009 – a more than sixfold increase in 20 years [1]. In the same time period, oxycodone consumption escalated from 10 to 77 tons. These data primarily reflect the increasing use in highly developed
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industrialized nations, including Austria, Canada, the USA, New Zealand and Australia. In stark contrast, opioids, even for the most basic treatment of acute and cancer pain, are almost inaccessible in a large number of countries [15]. Reasons for the increase are not so much evidence based, but driven by possibly incorrect concepts of chronic pain management [16], the availability of increasing numbers of slow-release and potentially even more dangerous immediate-release opioid preparations and promotion of opioid use for chronic nonmalignant pain by the pharmaceutical industry [17]. Other contributing factors are the increasing number of patients who are maintained in drug substitution programs for the treatment of opioid addiction. With regard to the patterns of illicit drug use, there seems to be stable use of heroin and in parallel an increase in the use of prescription opioids [18]. General considerations As with all other patients in an acute painful situation, provision of appropriate pain relief is the first goal. However, in opioid-tolerant patients there is also an important issue with regard to the prevention of withdrawal, as withdrawal
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REVIEW Schug Box 1. Causes of opioid tolerance in patients. Patients with cancer pain on opioid therapy This patient group is increasing in size with the improving survival rates of cancer The patients are often on very stable doses for a long time and usually have very well managed pain states Patients on long-term opioid therapy for chronic pain of nonmalignant origin This group of patients is currently rapidly increasing in size due to the increasing preparedness of the medical system to treat these pain states with opioids Patients are, in many cases, on surprisingly high opioid doses or rapidly escalating doses (>100 mg morphine equivalents/day), often have poorly controlled pain due to the poor responsiveness of many chronic pain states to opioids and show, in many studies, a high rate of abuse and aberrant drug taking behavior Patients for longer-term management of acute pain These patients include those requiring multiple operations after severe trauma or patients in the rehabilitation period after trauma and surgery They are often on high opioid doses short term, but long enough to develop opioid tolerance and associated problems Patients with a substance abuse disorder on opioid maintenance treatment These patients are often on high doses of methadone or buprenorphine in a controlled setting but have multiple comorbidities of a physical and psychiatric nature Despite opioid substitution, they often continue with polysubstance abuse of other drugs, such as benzodiazepines and amphetamines, which pose additional problems in the acute pain phase Patients with a substance abuse disorder not in a substitution program and continuing to use illicit opioids These patients pose significant problems in the acute pain management phase as they are not always forthcoming about their drug use, are not using defined doses of pharmacy grade opioids and often have significant psychosocial problems, psychiatric and physical comorbidities, including consequences of intravenous use of contaminated drugs (e.g., abscesses, ischemic events and endocarditis) Patients who are currently abstinent after previous opioid use or addiction These patients are no longer opioid-tolerant, but have achieved abstinence as a consequence of a drug treatment program or due to naltrexone therapy Challenges here are the concerns of the patient to relapse after exposure to opioids and the problems associated with the treatment of patients with a highly potent opioid antagonist for acute pain episodes
symptoms in the perioperative period can add significant distress for the patient [7]. In view of the high rate of often severe psychiatric comorbidities and relevant psychosocial issues, in particular in patients with addiction, these issues also need to be properly addressed. This summary of goals makes it obvious that these patients will often require a multidisciplinary and multimodal approach that not only requires the involvement of anesthetists and surgeons, but often also of pain medicine specialists, psychiatrists, clinical psychologists, addiction medicine personnel and social workers. However, this team approach needs to be carefully coordinated to avoid conflict between team members, and between the team and the patient. This is particularly important, as a subgroup of these patients can be rather manipulative and thereby leads to ‘team splitting’ [19]. Furthermore, the management of these patients requires careful planning before, during and after the painful episode, including appropriate discharge planning [7]. Therefore, early identification of the at-risk population is mandatory; hearing about an opioid-tolerant patient only when they reach the
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operating theaters is fraught with difficulties and problems. Once a patient has been identified as being opioid tolerant, necessary steps should be taken in the preoperative period to guarantee effective analgesic treatment throughout the acute pain phase and prevention of withdrawal symptoms and complications. Early involvement of multidisciplinary members of the team can be useful. Additional efforts must be made to manage aberrant drug-taking behavior in the acute pain phase, particularly as this can result in accidental overdose with significant risks. Last, but not least, preparation for discharge and hand over to primary care providers or, if appropriate, drug abuse services, with appropriate provision of acute pain medication and organization of maintenance opioids is necessary [5]. Assessment & preoperative planning As mentioned above, it is important to identify patients early in the setting of elective surgery [20]. Similarly, in situations of trauma or acute disease requiring acute pain management, patients need to be carefully assessed and this assessment needs to be well documented.
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Acute pain management in the opioid-tolerant patient It is important that the assessment is objective and that conversation with the patient is nonjudgmental and reassuring [7]. This is particularly important as these patients often have severe anxiety about the insufficient pain relief or the withdrawal symptoms they might have experienced in the past [21]. It is, therefore, essential that the initial conversation covers these issues and assures the patient that they will be provided with the best analgesia possible, while at the same time preventing withdrawal symptoms [7]. These reassurances should be convincing and are easy to achieve with regard to prevention of withdrawal. It is important to explain that it might be impossible to achieve freedom of pain, but that significant pain reduction is possible [4]. In opioid-tolerant patients, one has to expect increased pain scores in comparison to opioid-naive patients, and pain relief is usually required for longer periods [22,23]. It is important to develop a trusting relationship, as patients should be encouraged not to withhold information on aberrant drug-taking behavior or illicit drug use in the interests of a successful provision of analgesia and prevention of withdrawal and/or overdose [6]. Patients need to be asked in detail about all relevant medications, including nonprescribed drugs and the use of alcohol, nicotine and illicit drugs. In the interest of patient safety it is important to verify the types and doses of all relevant medications prescribed, in particular in patients on drug substitution programs [7]. Continuation of opioids at nonverified doses can carry a significant risk of overdose for the patient. Even the use of verified doses carries a certain risk, as diversion of opioids could mean that patients are not taking the prescribed drugs. In patients with chronic pain or cancer pain it is also important to enquire about the pain diagnosis and the usual pain intensity, and their functional status as a baseline. In patients with an underlying addiction it is not only important to verify the opioid substitution therapy, but also to ask detailed questions about other prescribed or illicit drug use in view of the high incidence of polysubstance abuse. These patients often also suffer from medical and psychiatric comorbidities that need to be evaluated in detail. In the preoperative phase, as well as throughout the subsequent management, one of the main prerequisites for success is the continuation of all opioids at the doses routinely taken by the patient. This continuation should be ideally via
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the route of administration usually used by the patient. However, in situations where oral intake is impossible, a switch to parenteral maintenance opioid therapy, ideally by continuous infusion of equianalgesic doses under consideration of pharmacokinetics and bioavailability, is mandatory. Provision of acute pain management Even more than in other patients, the basis for successful pain management in opioid-tolerant patients must be the utilization of multimodal analgesia strategies [24]. This approach should utilize nonopioid analgesics, such as paracetamol/acetaminophen and nonselective NSAIDs or selective COX-2 inhibitors, as well as the use of regional anesthesia and analgesia techniques. Furthermore, the use of antihyperalgesic medications, such as the NMDA receptor antagonist ketamine and/or the α-2-δ subunit modulators gabapentin and pregabalin, should be considered early. Nevertheless, it is important to assess patients with increased pain scores to avoid overlooking surgical or medical causes for increased pain. Opioids
Even in opioid-tolerant patients, it is necessary to rely on the use of opioids for severe pain. However, particularly in drug-substitution patients on very high doses of methadone, most opioid receptors are occupied by methadone and additional opioids might be of only limited efficacy. In all situations, opioid-tolerant patients will have increased opioid requirements, which are in the range of 30–100% more than for opioid-naive patients [25]; one study even identified a threefold increase of opioid requirements on average [23]. As in all other patients, opioids should be titrated to effect and adverse effects. This is most easily done by the use of patientcontrolled analgesia devices. Opioid-tolerant patients will require increased bolus doses with this technique. While continuous infusions of opioids as a background to patient-controlled analgesia are not recommended in opioid-naive patients, they can become necessary in opioidtolerant patients to cover background requirements if the oral route is not available [5]. Opioidtolerant patients are also tolerant to many adverse effects; however, it seems they are more sensitive to sedation with increased opioid consumption [23]. While the risk of respiratory depression is potentially not high, nevertheless, it needs to be considered in the monitoring of these patients.
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REVIEW Schug In particular, in situations of poor opioid responsiveness, the use of tramadol can be recommended [5] as its effects rely only to some extent on the opioid receptor, and more on monaminergic effects. No cross tolerance to morphine has been confirmed in animal models [26]. Nonopioid analgesics
It is well documented in opioid-naive patients that paracetamol/acetaminophen is opioid sparing [27]. The same is true for nonselective NSAIDs and selective coxibs, which not only have an opioid-sparing effect, but also reduce pain intensity and adverse effects of opioids in opioid-naive patients [28]. Therefore, it is logical to transfer this experience to the opioid-tolerant patients; they should be provided with perioperative paracetamol/acetaminophen at maximum daily doses and with appropriate use of nonselective NSAIDs or because of the superior adverse event profile, preferably selective COX-2 inhibitors [29]; the combination provides superior analgesia [30]. Regional techniques
Regional analgesia techniques, particularly via infusion through the peripheral nerve or epidural catheters, provide excellent analgesia without reliance on the opioid-receptor system. Regional analgesia techniques should therefore be employed with preference in opioid-tolerant patients, as they can provide best possible analgesia to these patients without relying on opioid receptor effects; reliability can be increased by using ultrasound guided techniques and the duration of effect can be extended by infusion of local anesthetics via nerve catheters. However, it is important to realize that regional analgesia techniques, even if they include epidural opioid administration, are insufficient to prevent withdrawal [5]. Even in pain-free patients, the ongoing supplementation with their usual opioids in their usual doses is mandatory. Antihyperalgesic medications
The NMDA receptor antagonist ketamine has been widely used to improve pain relief in acute pain situations [31]. In particular, this medication might be useful in patients who are opioidtolerant. The theoretical considerations in favor of the use of ketamine as an adjunct in opioidtolerant patients have been confirmed in randomized controlled trials, which showed opioid sparing and/or improved analgesia with the use
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of patient-controlled analgesia on the background of a continuous ketamine infusion [32,33]. The α-2-δ subunit modulators, pregabalin and gabapentin, have proven antihyperalgesic properties, for example, in the management of neuropathic pain and fibromyalgia. Premedication with these compounds in the opioid-naive patient results in improved analgesia, reduced opioid consumption and reduced incidence of adverse effects of opioids [34,35]. The substances have also been shown to be effective in reducing opioid-induced hyperalgesia in animal experiments [36] and in a human study [37]. On the basis of this evidence it is reasonable to recommend that gabapentin, or preferably pregabalin because of its superior pharmacok inetics, should be used in the perioperative management of opioid-tolerant patients. An additional advantage might be the reduction of persistent postsurgical pain, as shown in a recent meta-analysis [38]. Prevention of withdrawal Besides the provision of acute pain relief, another important goal in opioid-tolerant patients is the prevention of withdrawal. This is best achieved by continuation of previous opioids in their established long-term dosages. As outlined before, substitution needs to be changed to an equianalgesic dose via the parenteral route if oral intake is not possible in the early postoperative or postinjury period. Furthermore, the use of opioid antagonists, such as naloxone, needs to be avoided under all circumstances [39]. Clonidine can be a useful adjunct in the management of such symptoms [40]. However, clonidine also has adverse effects, such as sedation and hypotension, which need to be considered if it is used to manage withdrawal symptoms. Therefore, prevention of such symptoms by opioid use and titration of opioids against withdrawal symptoms is the better strategy. It is of note that many patients who are abusing opioids are also abusing other substances and can therefore develop withdrawal symptoms, in particular with regard to benzodiazepines and alcohol in the acute phase. In severe cases, these withdrawal symptoms can even be life threatening and require appropriate titration of benzodiazepines, and might again be helped by the use of clonidine. Special considerations in patients on drug
substitution programs
The two most commonly used opioids for the substitution therapy of drug addiction are methadone
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Acute pain management in the opioid-tolerant patient and buprenorphine; only very few countries permit supervised parenteral heroin administration in patients with severe addiction problems. With regard to methadone, there is consensus that the substitution dose of methadone should be continued throughout the acute pain episode. However, as the analgesic effect of methadone is not as long lasting as the substitution effect in many patients, it is standard practice in many services to split the daily methadone dose and provide one-third of the dose every 8 h to achieve best possible analgesic benefit from this medication [41]. If patients have to be kept nil by mouth then methadone needs to be substituted parenterally [20]. The authors’ preferred route is to give a continuous intravenous infusion of 60% of the daily oral dose. There is considerable variability with regard to the attitude towards increasing the substitution dose of methadone in acute pain situations. Some abuse services prefer a clear separation of substitution from analgesia and suggest, therefore, the use of a different opioid to provide analgesia. Other services are more liberal and permit dose increases of the substitution opioid, methadone, to provide improved analgesia in the acute phase. There is no e vidence in favor of one or the other approach. With regard to buprenorphine, the confusion is even more wide ranging. While buprenorphine is pharmacologically characterized as a partial µ-agonist and κ-antagonist, its properties in the clinical setting are similar to other µ-agonist opioids; however, with high opioid-receptor affinity and long duration of binding to the receptor. Therefore, the literature is filled with conflicting recommendations with regard to the continuation or discontinuation of buprenorphine substitution through an acute pain episode. A number of publications quoted in a review that are not based on reliable evidence are concerned about the potential of buprenorphine, with its high receptor affinity and potential antagonistic effects, to block access of full µ-agonists to the opioid receptors and thereby prevent effective analgesia [25]. Therefore, they recommend ceasing buprenorphine in the perioperative period [21]. However, this is not the experience of others [7,42]. Two published case series show that maintaining sublingual buprenorphine substitution throughout an acute pain episode does not preclude opioids from being effective with similar opioid consumption and pain scores in patients on buprenorphine or methadone [43,44]. In line with these observations, we agree to the
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recommendation that buprenorphine maintenance therapy should be continued throughout acute pain episodes [7]. Again, as with methadone, it might be useful to split the daily dose into three doses taken in 8-hourly intervals, as analgesia might not be as long lasting as suppression of opioid withdrawal [39]. We have even successfully increased the buprenorphine maintenance dose in selected patients on high opioid requirements and have not seen impairment of the effect of other opioids used in this setting. Special considerations in patients using
illicit opioids
This rule of maintaining background opioids is most difficult to achieve in patients with a current addiction who are continuing to use illicit opioids, be it heroin or prescription opioids. The issues here are that a stable maintenance dose cannot be easily established, as it depends on the usage pattern of the individual patient and the availability of different purities of heroin respective to different mixtures of prescription opioids. One recommended approach is the use of methadone in doses of 5–10 mg as required to prevent withdrawal symptoms [25]. Management of social issues The management of opioid-tolerant patients cannot exclusively rely on pharmacological intervention. As outlined above, many opioid-tolerant patients, in particular those exhibiting aberrant drug-taking behavior or blatant addiction, suffer from a considerable number of psychiatric comorbidities. In addition, there are often multiple unresolved psychosocial issues ranging from homelessness to ongoing intravenous drug use to abusive behavior. Key issues, particularly in the addicted patients, are that they are often extremely fearful of withdrawal and of unrelieved pain [4]. In addition, these patients often do not cope well with stress and, therefore, show overshooting stress response in the acute painful situation. On the other hand, such patients are often stigmatized by medical and nursing personnel [21]. This is often caused by the difficulties to differentiate drug-seeking behavior from patients’ requests for additional opioids for genuine pain relief; mistaking the latter for addictive behavior has led to the term pseudoaddiction [45]. If patients show behavioral problems, one should always exclude withdrawal [7]. Other issues leading to conflict are manipulation by these patients and a team-splitting
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REVIEW Schug effect, as well as the diversion of opioids provided (e.g., by not taking opioid tablets, but hoarding them) or the illicit use of opioids on the ward (e.g., by injecting oral preparations that were hoarded or supplied by friends, relatives and visitors) [19]. The keys for success are, therefore, the good training of all involved personnel, a team approach, and consistent communication between both the team members themselves, and between the team members and the patient. It is important to outline a treatment plan with thresholds and limits for behavioral aberration [7]. These rules need to be stated clearly and enforced; formulation of these limits in a treatment agreement can be helpful. Special considerations in previously opioid-dependent patients Patients who have successfully participated in drug treatment programs and are now ‘clean’ are no longer on any substitution program. They are extremely fearful of re-exposure to opioids in view of the perceived risk of re-induction of opioid dependence and addiction [25]. These fears need to be addressed in a detailed conversation prior to the need for acute pain relief. In addition, these patients might suffer from a protracted abstinence syndrome that can last for weeks or months, sometimes even years. This syndrome is characterized by a latent neuronal hyperexcitability with increased sensitivity to opioids and, in particular, increased adverse effects [46]. The ideal approach to the provision of acute pain relief in these patients is the use of nonopioid analgesics, appropriate adjuvants and regional anesthesia and analgesia [21]. If this approach is insufficient to provide pain relief then the use of tramadol can be recommended, as even parenteral administration of analgesic doses of tramadol do not lead to recognition of opioid effects in experienced opioid users [47]. However, it will not always be possible to get through a period of severe acute pain with complete avoidance of opioids. It is important to explain to the patient that opioid exposure for pain relief is not necessarily a risk factor for reoccurrence of addiction. On the contrary, there are data to suggest that insufficient pain relief is a more important risk factor here [39]. In the postoperative period, opioids can be titrated; however, more care might be needed with titration than is needed for opioidnaive patients due to the increased sensitivity to opioids in p rotracted abstinence.
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Discharge planning & ongoing management Opioid-tolerant patients who have gone through a period of acute pain, usually as inpatients in a hospital, require careful discharge planning and, in particular, excellent communication with the primary healthcare provider or the drug abuse program the patient is enrolled in [7]. Ideally, chronic pain patients should be discharged on the medication in the doses they were admitted on and this should be communicated with the original prescriber to guarantee ongoing supply. However, this approach might be different if the prescribed opioid amounts seem inappropriate or aberrant drug-taking behavior, including diversion, was identified during the hospital stay. In these cases, the situation needs to be discussed with the patient and the primary prescriber. In extreme cases of diversion or aberrant drug-taking behavior information of the authorities and the involvement of a drug abuse service may be appropriate. Similarly, patients in substitution programs should ideally be discharged on the previously used substitution opioid in the previously established dose and dosing interval. Again, informing the prescriber in the drug abuse program and the dispensing pharmacy are necessary to guarantee ongoing prescribing. Patients who were identified as being opioid tolerant due to illicit opioid use should ideally be referred to a drug abuse service while in hospital. Depending on the legal situation and the infrastructure, such patients who are usually established on an opioid regimen during their hospital stay, commonly using methadone, should sub sequently be transferred into the care of a methadone substitution program. Such approaches are significantly facilitated by the early involvement of a drug abuse service while the patient is in hospital. However, many patients will be discharged from hospital, especially now, with increasing pressures to reduce hospital stay, when their acute pain has not completely resolved. The provision of ongoing analgesia for such an acute pain episode in the out-of-hospital period requires careful planning and good liaison with the primary care providers of the patient. It is recommended that all nonopioid analgesics, and possibly an antihyperalgesic compound, such as pregabalin, is continued upon discharge to achieve maximum opioidsparing effects. Tramadol is possibly a good choice for provision of ongoing analgesia if requirements are not too high [7]. This view is supported by animal studies and review literature, and is also the clinical experience of the author and many
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Acute pain management in the opioid-tolerant patient other clinicians. The risk of diversion is low and the provision of analgesia through nonopioid mechanisms is effective [5]. Nevertheless, there will be patients who require increased opioid provision in the early period after discharge [7]. Here, a number of considerable problems can be encountered. From a medico–legal point of view, the prescription of opioids to patients with an addiction disorder or on a substitution program by doctors other than drug abuse specialists is illegal in a number of countries. Furthermore, a supply of large quantities of immediate-release opioids carries the risk of potential diversion, or deliberate or accidental overdose. Doctors have a poor record of predicting such behavior [48]. Therefore, precautions need to be taken when immediate-release opioids are prescribed for breakthrough pain to such patients. Such precautions include limited supply, possibly daily pick up of limited amounts from a pharmacist, a detailed weaning schedule and discussion with the primary healthcare provider involved [7]. Consideration should be given to increase the dose of the slow-release opioid or even the substitution opioid to provide pain relief, instead of the supply of immediate-release opioids. It is nearly impossible to provide universal rules or standard operating procedures for these situations and an individual decision should be made in close cooperation between the hospital team involved and the providers of healthcare in the out-of-hospital setting [7]. Conclusion & future perspective The number of opioid-tolerant patients requiring acute pain relief is increasing worldwide. Such patients are opioid tolerant due to longterm exposure to opioids for the treatment of chronic cancer and noncancer pain, the illicit intake of opioids or the substitution of such opioids in addiction, and rarely due to short-term management of protracted acute pain episodes. The management of these patients is currently mainly empirical and based on experience, case series and anecdotes, as evidence is lacking. There is consensus that these patients require a multimodal approach with support by a multidisciplinary team to achieve the best results. As a general rule, the previously established opioid therapy and opioid dose should be continued throughout the acute pain episode. Despite this approach, opioid-tolerant patients tend to experience more pain and have higher analgesic requirements than opioid-naive patients.
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The provision of analgesia should rely as much as possible on the use of regional analgesia techniques and systemic multimodal analgesia involving the use of nonopioid analgesics and compounds with antihyperalgesic effects. However, opioid usage cannot always be avoided, and then titration of opioid to effect and adverse effects is even more important than in opioid-naive patients. Opioid-tolerant patients will require higher opioid doses to achieve analgesia. Another important treatment goal is the prevention of withdrawal, which is ideally achieved by maintaining background opioids; rarely, the treatment of withdrawal symptoms with clonidine might be indicated. Throughout the acute pain episode, psychosocial and psychia tric issues, and other comorbidities need to be managed appropriately by involvement of other team members. These patients require careful discharge planning to facilitate the transfer to their primary care provider or drug abuse service. With regard to future directions there is an obvious need for more intense and better performed research into this area. The current lack of evidence in view of the large number of patients concerned is worrying and needs to be addressed. Well-designed randomized trials on the most appropriate measures and the usefulness of antihyperalgesic agents need to be performed. Specifically, the question of how to manage patients on buprenorphine maintenance therapy requires detailed assessment in view of the increasing popularity of this treatment for patients with addiction disorders. Furthermore, it might be that, in the future, the number of opioid-tolerant patients might actually decrease in view of the current change in attitudes towards the management of chronic pain of nonmalignant origin with opioids. After the initial undesirable opiophobia of the 1980s, we are now obviously at a peak of opioid consumption in the developed world, which, particularly in the setting of chronic pain of nonmalignant origin, is not supported by the available evidence [12]. The current development of more conservative treatment guidelines for the management of these patients and the development of risk evaluation and harm-minimization programs in view of the considerable societal problems that have been caused by inappropriate and excessive opioid prescribing might lead to a reduction in the number of patients on opioids long term, in particular those on high doses.
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Financial & competing interests disclosure The Anaesthesiology Unit of the University of Western Australia has received research and travel funding, and speaking and consulting honararia from CSL, Eli Lilly, Gruenenthal, iXBiopharma, Janssen Pharmaceuticals, Mundipharma and Pfizer within the last 2 years. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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International Narcotics Control Board. Report of the International Narcotics Control Board for 2009. United Nations, NY, USA (2010). Okie S. A flood of opioids, a rising tide of deaths. N. Engl. J. Med. 363(21), 1981–1985 (2010). A chilling summary of the problem of increasing opioid prescribing in the USA and its terrible consequences – a must-read for every doctor involved in pain management. Soderstrom CA, Ballesteros MF, Dischinger PC, Kerns TJ, Flint RD, Smith GS. Alcohol/ drug abuse, driving convictions, and risk-taking dispositions among trauma center patients. Accid. Anal. Prev. 33(6), 771–782 (2001). Roberts LJ. The opioid-tolerant patient, including those with a substance abuse disorder. In: Clinical Pain Management: Acute Pain. Macintyre PE, Walker SM, Rowbotham DJ (Eds). Hodder Arnold, London, UK, 560–579 (2008). Acute Pain Management: Scientific Evidence. Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM (Eds). Australian and New Zealand College of Anaesthetists, and Faculty of Pain Medicine, Melbourne, Australia (2010). A summary of all evidence pertaining to acute pain management with specific chapters on the opioid-tolerant patient. Also available at: www.fpm.anzca.edu.au/ resources/books-and-publications Bourne N. Acute pain management in the opioid-tolerant patient. Nurs. Stand. 25(12), 35–39 (2010).
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management of acute pain in the opioiddependent patient. Anesthesiology 101(1), 212–227 (2004). 21 Lerchl-Wanie G, Angster R. Perioperative
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D, Billharz J. Postoperative pain patterns in chronic pain patients: a pilot study. Pain Med. 10(3), 481–487 (2009). 23 Rapp SE, Ready LB, Nessly ML. Acute pain
management in patients with prior opioid consumption: a case-controlled retrospective review. Pain 61(2), 195–201 (1995). 24 Buvanendran A, Kroin JS. Multimodal
analgesia for controlling acute postoperative pain. Curr. Opin. Anaesthesiol. 22(5), 588–593 (2009). 25 Jage J, Heid F. Anesthesia and analgesia in
addicts: basis for establishing a standard operating procedure. Anaesthesist 55(6), 611–628 (2006). 26 Kayser V, Besson JM, Guilbaud G. Effects of
the analgesic agent tramadol in normal and arthritic rats: comparison with the effects of different opioids, including tolerance and cross-tolerance to morphine. Eur. J. Pharmacol. 195(1), 37–45 (1991). 27 Remy C, Marret E, Bonnet F. Effects of
acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br. J. Anaesth. 94(4), 505–513 (2005). 28 Marret E, Kurdi O, Zufferey P, Bonnet F.
Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: meta-analysis of randomized controlled trials. Anesthesiology 102(6), 1249–1260 (2005). 29 Schug SA. The role of COX-2 inhibitors in
the treatment of postoperative pain. J. Cardiovasc. Pharmacol. 47(Suppl. 1), S82–S86 (2006). 30 Ong CK, Seymour RA, Lirk P, Merry AF.
Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs:
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pregabalin in acute postoperative pain: a meta-analysis. Br. J. Anaesth. 106(4), 454–462 (2011).
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preventing fentanyl- and morphinewithdrawal-induced hyperalgesia in rats. J. Anesth. 26(2), 236–241 (2012). 37 Jo HR, Chae YK, Kim YH et al.
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and withdrawal in the critical care setting. Crit. Care Clin. 24(4), 767–788, viii (2008). 41 Basu S, Bruce RD, Barry DT, Altice FL.
Pharmacological pain control for human immunodeficiency virus-infected adults with a history of drug dependence. J. Subst. Abuse Treat. 32(4), 399–409 (2007).
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Kalso E. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth. Analg. 104(6), 1545–1556, table of contents (2007).
buprenorphine undergoing major surgery: a case series. Am. J. Ther. 17(5), 523–528 (2010).
M, Wijeysundera DN, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth. Analg. 115(2), 428–442 (2012).
HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can. J. Anaesth. 58(10), 911–923 (2011). Lipnitsky JY. Ketamine as an adjunct to postoperative pain management in opioid tolerant patients after spinal fusions: a prospective randomized trial. HSS J. 4(1), 62–65 (2008).
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A comparison of postoperative opioid requirements and effectiveness in methadoneand buprenorphine-maintained patients. Anaesth. Intensive Care 39, 726–727 (2011). pseudoaddiction – an iatrogenic syndrome. Pain 36(3), 363–366 (1989). 46 Strang J, McCambridge J, Best D et al.
Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study. BMJ 326(7396), 959–960 (2003). 47 Preston KLJC, Jasinski DR, Testa M.
Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend. 27(1), 7–17 (1991). 48 Jung B, Reidenberg MM. Physicians being
deceived. Pain Med. 8(5), 433–437 (2007). 49 American Academy of Pain Medicine, the
American Pain Society and the American Society of Addition Medicine. Definitions related to the use of opioids for the treatment of pain. WMJ 100(5), 28–29 (2001). 50 Ballantyne JC, LaForge KS. Opioid
dependence and addiction during opioid treatment of chronic pain. Pain 129(3), 235–255 (2007). 51 Fishbain DA, Cole B, Lewis JE, Gao J,
Rosomoff RS. Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Med. 10(5), 829–839 (2009).
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Practice Points
Stephan A Schug* Opioid-tolerant patients are using opioids long term to treat cancer and/or chronic pain, or are addicted
to opioids they use illicitly or in drug substitution programs. Opioid-tolerant patients experience more severe pain for longer periods of time and require higher
opioid doses in acute pain situations. Due to the complexity of their situation, including psychiatric and medical comorbidities, these patients
require a coordinated multidisciplinary approach with good communication between team members and the patient. Principles of acute pain treatment in opioid-tolerant patients are provision of good analgesia, prevention
of withdrawal and discharge planning. Provision of good analgesia relies on a multimodal approach based on the use of nonopioid analgesics
(paracetamol/acetaminophen, NSAIDs or COX-2 inhibitors), antihyperalgesics (ketamine, gabapentin or pregabalin) and regional analgesia with titrated opioid use. Prevention of withdrawal is best achieved by continuation of preadmission opioid regimens, including
substitution with methadone and buprenorphine. Discharge planning requires liaison with all healthcare providers involved to provide appropriate
analgesia and continue opioid supply, while preventing diversion and accidental or intentional overdose.
SUMMARY Opioid use is increasing worldwide leading to an increasing number of opioid-tolerant patients requiring acute pain management after surgery, trauma and acute diseases. Provision of analgesia in opioid-tolerant patients is complex due to the pharmacological effects of long-term opioid exposure, but also due to pre-existing pain states, comorbidities and psychosocial issues. Acute pain management in these patients is governed by the principles of provision of good analgesia, avoidance of withdrawal and organized discharge. Pain relief needs to be achieved by the use of multimodal analgesia, including regional anesthetic techniques and, if needed, opioids in increased doses. Withdrawal is best *Pharmacology & Anaesthesiology Unit, School of Medicine & Pharmacology, University of Western Australia, Australia and Department of Pain Medicine, Royal Perth Hospital, UWA Anaesthesia, Level 2, MRF Building G Block, Royal Perth Hospital, GPO Box X2213, Perth WA 6847, Australia Tel.: +61 8 9224 0201; Fax: +61 8 9224 0279; [email protected]
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The number of opioid-tolerant patients who need treatment for acute pain is increasing worldwide. This is due to a combination of the following factors: worldwide opioid consumption is increasing significantly [1]; more cancer pain patients survive longer and get better analgesia; opioid use in chronic pain of nonmalignant origin is increasing significantly [2]; and there is a large group of patients who are either abusing opioids or are on substitution opioids for previous opioid abuse. In addition, patients who are abusing opioids or are on substitution programs have an increased risk of trauma and significant comorbidities requiring surgical intervention, which leads to a further increase in the numbers of such patients requiring acute pain management [3]. In view of the pharmacological considerations and, often even more so, the accompanying psychosocial issues, these patients are usually complex and require significant, often multidisciplinary, input to achieve good outcomes [4]. This situation is further complicated because the scientific evidence for managing these patients is poor [5]. Therefore, a lot of the treatment is more experience than evidence based and the anecdotal evidence might be flawed or unsupported. It is not surprising that a recent review on this topic was published in the ‘Art & Science’ section of a journal [6]. However, there is general agreement that patients who are opioid tolerant require provision of excellent analgesia and appropriate measures to prevent withdrawal, as they are often already affected by anxiety, depression and other psychiatric comorbidities [7]. Not relieving their pain appropriately can result in a dramatic increase of such problems in the face of acute injury or postsurgery, when patients often have difficulty coping anyway. The stigma of drug abuse and the perception of inappropriate opioid use in many opioid-tolerant patients govern the thinking of medical and nursing staff [4]. Often significant prejudices are obvious and lead to inappropriate comments and neglect of pain relief required [8]. In addition, there are often large deficits in education and training of personnel involved in these cases. Both the prejudice and the lack of education and training carry the risk of mistaking reports of pain as seeking opioids or having withdrawal symptoms. Furthermore, there is the risk of not
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recognizing withdrawal symptoms and intoxication and not separating these from other pathologies. Last, but not least, it is totally inappropriate, but attempts are sometimes made to treat addiction in the acute period after trauma or surgery, and such attempts can lead to further problems. The correct approach to the acute pain management of the opioid-tolerant patient requires knowledge, experience and empathy, but also clear directions to avoid major rifts among members of the treating team and additional behavioral problems [7]. The following review attempts to summarize the current, albeit limited, know ledge on the management of acute pain in this diverse but often difficult group of patients. Definitions This review will deal with the issues of acute pain management in opioid-tolerant patients. Acute pain management can become necessary in the postoperative period, after trauma and in patients with acute diseases causing pain. Opioid-tolerant patients are patients who have been exposed to opioids for long periods of time; most data suggest that continuous exposure to opioids for 10–14 days results in the development of tolerance [9]. Tolerance is only one of the phenomena observed in these patients; there are a number of other issues that complicate their management. These include physical dependence, addiction, pseudoaddiction, opioid-induced hyperalgesia and, as a consequence of these, withdrawal symptoms and craving. Definitions of these and other relevant terms are provided in Table 1. Patients can be opioid tolerant for a variety of reasons; a list can be found in Box 1. Size of the problem As mentioned previously, licit opioid consumption is increasing rapidly. This development has been primarily led by developments in the USA; here 4.6% of the world population consume 80% of the licit global opioid supply [10]. Reasons are, to some extent, the more aggressive and longerlasting treatment of cancer survivors, but to a much larger extent, the increasing preparedness of the medical community to treat chronic pain of nonmalignant origin with opioids [11]. This trend may be justified for defined nociceptive (e.g.,
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Table 1. Definitions of relevant terms. Term
Definition
Tolerance
A decrease in the effectiveness of a drug over time with prolonged intake. This leads to an increase in requirements for the drug to achieve the same effect or decrease in effectiveness with maintaining a stable drug dose. Tolerance to many drugs can develop and can be based on pharmacokinetic and pharmacodynamic factors. Tolerance can develop to some, but not all, effects of a drug, and can develop at different rates A physiological phenomenon with prolonged intake of a drug that leads to withdrawal symptoms when the drug is abruptly discontinued, reduced in dose or antagonized. This is a pharmacological and not a psychological mechanism and can develop both to drugs with a psychotropic effect (e.g., opioids) as well as to other drugs (e.g., β blockers) Addiction is commonly defined as a disease characterized by aberrant drug seeking and maladaptive drug taking behaviors, and loss of control over drug use despite obvious physical, social and psychological harm. Addiction is not necessarily connected to the pharmacological phenomena of tolerance and physical dependence, but can be reinforced by these. It is important to note that tolerance and physical dependence are predictable effects of a given drug, while addiction is influenced not only by the addiction liability of a specific drug, but also by psychological, social, environmental and genetic factors in the user An iatrogenic syndrome of abnormal behavior developing as a direct consequence of inadequate pain management. This is often the direct result of inadequately prescribed or inadequately provided analgesia, but misread as drug seeking and presenting with overarching pain behavior to obtain more opioids Symptoms of varying severity after complete or incomplete withdrawal of a psychotropic substance that had been previously used long term. Withdrawal symptoms to opioids include agitation, restlessness, anxiety, dysphoria and hyperalgesia, in particular with abdominal pain, hypertension, tachycardia, increased respiratory drive, diarrhea, muscle spasms, increased sensitivity to cold, gooseflesh and mydriasis [40]. They reflect the increased neuronal excitation after removal of a CNS-dampening substance Strong desire to obtain a psychotropic substance Opioid use may paradoxically lead to an increased sensitivity to pain. This phenomenon has been described with short- and long-term use of various opioids, primarily in animal and volunteer experiments. The relevance for the clinical setting is currently heavily debated
Physical dependence Addiction
Pseudoaddiction
Withdrawal symptoms
Craving Opioid-induced hyperalgesia
Adapted from [5,21,25,45,49–51].
osteoarthritis) and neuropathic (e.g., postherpetic neuralgia) pain states, but is not necessarily supported by evidence for the management of dysfunctional pain conditions, such as fibromyalgia, nonspecific chronic low back pain and interstitial cystitis [12]. Nevertheless, patients with these conditions are prescribed increasing doses of opioids long term with significant implications, not only with regard to the development of tolerance, but also potentially opioid-induced hyperalgesia. Other consequences are the increasing problems with diversion of licitly prescribed opioids into the illicit market [13]. Prescription opioids have not only become the most common drugs abused in many countries, but are also contributing to an increasing rate of prescription drugrelated overdoses with significant mortality [14]. It is hard to describe the situation better than a paper in The New England Journal of Medicine titled “A flood of opioids, a rising tide of death” [2]. Morphine consumption worldwide increased from 7 tons in 1989 to 42 tons in 2009 – a more than sixfold increase in 20 years [1]. In the same time period, oxycodone consumption escalated from 10 to 77 tons. These data primarily reflect the increasing use in highly developed
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industrialized nations, including Austria, Canada, the USA, New Zealand and Australia. In stark contrast, opioids, even for the most basic treatment of acute and cancer pain, are almost inaccessible in a large number of countries [15]. Reasons for the increase are not so much evidence based, but driven by possibly incorrect concepts of chronic pain management [16], the availability of increasing numbers of slow-release and potentially even more dangerous immediate-release opioid preparations and promotion of opioid use for chronic nonmalignant pain by the pharmaceutical industry [17]. Other contributing factors are the increasing number of patients who are maintained in drug substitution programs for the treatment of opioid addiction. With regard to the patterns of illicit drug use, there seems to be stable use of heroin and in parallel an increase in the use of prescription opioids [18]. General considerations As with all other patients in an acute painful situation, provision of appropriate pain relief is the first goal. However, in opioid-tolerant patients there is also an important issue with regard to the prevention of withdrawal, as withdrawal
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REVIEW Schug Box 1. Causes of opioid tolerance in patients. Patients with cancer pain on opioid therapy This patient group is increasing in size with the improving survival rates of cancer The patients are often on very stable doses for a long time and usually have very well managed pain states Patients on long-term opioid therapy for chronic pain of nonmalignant origin This group of patients is currently rapidly increasing in size due to the increasing preparedness of the medical system to treat these pain states with opioids Patients are, in many cases, on surprisingly high opioid doses or rapidly escalating doses (>100 mg morphine equivalents/day), often have poorly controlled pain due to the poor responsiveness of many chronic pain states to opioids and show, in many studies, a high rate of abuse and aberrant drug taking behavior Patients for longer-term management of acute pain These patients include those requiring multiple operations after severe trauma or patients in the rehabilitation period after trauma and surgery They are often on high opioid doses short term, but long enough to develop opioid tolerance and associated problems Patients with a substance abuse disorder on opioid maintenance treatment These patients are often on high doses of methadone or buprenorphine in a controlled setting but have multiple comorbidities of a physical and psychiatric nature Despite opioid substitution, they often continue with polysubstance abuse of other drugs, such as benzodiazepines and amphetamines, which pose additional problems in the acute pain phase Patients with a substance abuse disorder not in a substitution program and continuing to use illicit opioids These patients pose significant problems in the acute pain management phase as they are not always forthcoming about their drug use, are not using defined doses of pharmacy grade opioids and often have significant psychosocial problems, psychiatric and physical comorbidities, including consequences of intravenous use of contaminated drugs (e.g., abscesses, ischemic events and endocarditis) Patients who are currently abstinent after previous opioid use or addiction These patients are no longer opioid-tolerant, but have achieved abstinence as a consequence of a drug treatment program or due to naltrexone therapy Challenges here are the concerns of the patient to relapse after exposure to opioids and the problems associated with the treatment of patients with a highly potent opioid antagonist for acute pain episodes
symptoms in the perioperative period can add significant distress for the patient [7]. In view of the high rate of often severe psychiatric comorbidities and relevant psychosocial issues, in particular in patients with addiction, these issues also need to be properly addressed. This summary of goals makes it obvious that these patients will often require a multidisciplinary and multimodal approach that not only requires the involvement of anesthetists and surgeons, but often also of pain medicine specialists, psychiatrists, clinical psychologists, addiction medicine personnel and social workers. However, this team approach needs to be carefully coordinated to avoid conflict between team members, and between the team and the patient. This is particularly important, as a subgroup of these patients can be rather manipulative and thereby leads to ‘team splitting’ [19]. Furthermore, the management of these patients requires careful planning before, during and after the painful episode, including appropriate discharge planning [7]. Therefore, early identification of the at-risk population is mandatory; hearing about an opioid-tolerant patient only when they reach the
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operating theaters is fraught with difficulties and problems. Once a patient has been identified as being opioid tolerant, necessary steps should be taken in the preoperative period to guarantee effective analgesic treatment throughout the acute pain phase and prevention of withdrawal symptoms and complications. Early involvement of multidisciplinary members of the team can be useful. Additional efforts must be made to manage aberrant drug-taking behavior in the acute pain phase, particularly as this can result in accidental overdose with significant risks. Last, but not least, preparation for discharge and hand over to primary care providers or, if appropriate, drug abuse services, with appropriate provision of acute pain medication and organization of maintenance opioids is necessary [5]. Assessment & preoperative planning As mentioned above, it is important to identify patients early in the setting of elective surgery [20]. Similarly, in situations of trauma or acute disease requiring acute pain management, patients need to be carefully assessed and this assessment needs to be well documented.
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Acute pain management in the opioid-tolerant patient It is important that the assessment is objective and that conversation with the patient is nonjudgmental and reassuring [7]. This is particularly important as these patients often have severe anxiety about the insufficient pain relief or the withdrawal symptoms they might have experienced in the past [21]. It is, therefore, essential that the initial conversation covers these issues and assures the patient that they will be provided with the best analgesia possible, while at the same time preventing withdrawal symptoms [7]. These reassurances should be convincing and are easy to achieve with regard to prevention of withdrawal. It is important to explain that it might be impossible to achieve freedom of pain, but that significant pain reduction is possible [4]. In opioid-tolerant patients, one has to expect increased pain scores in comparison to opioid-naive patients, and pain relief is usually required for longer periods [22,23]. It is important to develop a trusting relationship, as patients should be encouraged not to withhold information on aberrant drug-taking behavior or illicit drug use in the interests of a successful provision of analgesia and prevention of withdrawal and/or overdose [6]. Patients need to be asked in detail about all relevant medications, including nonprescribed drugs and the use of alcohol, nicotine and illicit drugs. In the interest of patient safety it is important to verify the types and doses of all relevant medications prescribed, in particular in patients on drug substitution programs [7]. Continuation of opioids at nonverified doses can carry a significant risk of overdose for the patient. Even the use of verified doses carries a certain risk, as diversion of opioids could mean that patients are not taking the prescribed drugs. In patients with chronic pain or cancer pain it is also important to enquire about the pain diagnosis and the usual pain intensity, and their functional status as a baseline. In patients with an underlying addiction it is not only important to verify the opioid substitution therapy, but also to ask detailed questions about other prescribed or illicit drug use in view of the high incidence of polysubstance abuse. These patients often also suffer from medical and psychiatric comorbidities that need to be evaluated in detail. In the preoperative phase, as well as throughout the subsequent management, one of the main prerequisites for success is the continuation of all opioids at the doses routinely taken by the patient. This continuation should be ideally via
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the route of administration usually used by the patient. However, in situations where oral intake is impossible, a switch to parenteral maintenance opioid therapy, ideally by continuous infusion of equianalgesic doses under consideration of pharmacokinetics and bioavailability, is mandatory. Provision of acute pain management Even more than in other patients, the basis for successful pain management in opioid-tolerant patients must be the utilization of multimodal analgesia strategies [24]. This approach should utilize nonopioid analgesics, such as paracetamol/acetaminophen and nonselective NSAIDs or selective COX-2 inhibitors, as well as the use of regional anesthesia and analgesia techniques. Furthermore, the use of antihyperalgesic medications, such as the NMDA receptor antagonist ketamine and/or the α-2-δ subunit modulators gabapentin and pregabalin, should be considered early. Nevertheless, it is important to assess patients with increased pain scores to avoid overlooking surgical or medical causes for increased pain. Opioids
Even in opioid-tolerant patients, it is necessary to rely on the use of opioids for severe pain. However, particularly in drug-substitution patients on very high doses of methadone, most opioid receptors are occupied by methadone and additional opioids might be of only limited efficacy. In all situations, opioid-tolerant patients will have increased opioid requirements, which are in the range of 30–100% more than for opioid-naive patients [25]; one study even identified a threefold increase of opioid requirements on average [23]. As in all other patients, opioids should be titrated to effect and adverse effects. This is most easily done by the use of patientcontrolled analgesia devices. Opioid-tolerant patients will require increased bolus doses with this technique. While continuous infusions of opioids as a background to patient-controlled analgesia are not recommended in opioid-naive patients, they can become necessary in opioidtolerant patients to cover background requirements if the oral route is not available [5]. Opioidtolerant patients are also tolerant to many adverse effects; however, it seems they are more sensitive to sedation with increased opioid consumption [23]. While the risk of respiratory depression is potentially not high, nevertheless, it needs to be considered in the monitoring of these patients.
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REVIEW Schug In particular, in situations of poor opioid responsiveness, the use of tramadol can be recommended [5] as its effects rely only to some extent on the opioid receptor, and more on monaminergic effects. No cross tolerance to morphine has been confirmed in animal models [26]. Nonopioid analgesics
It is well documented in opioid-naive patients that paracetamol/acetaminophen is opioid sparing [27]. The same is true for nonselective NSAIDs and selective coxibs, which not only have an opioid-sparing effect, but also reduce pain intensity and adverse effects of opioids in opioid-naive patients [28]. Therefore, it is logical to transfer this experience to the opioid-tolerant patients; they should be provided with perioperative paracetamol/acetaminophen at maximum daily doses and with appropriate use of nonselective NSAIDs or because of the superior adverse event profile, preferably selective COX-2 inhibitors [29]; the combination provides superior analgesia [30]. Regional techniques
Regional analgesia techniques, particularly via infusion through the peripheral nerve or epidural catheters, provide excellent analgesia without reliance on the opioid-receptor system. Regional analgesia techniques should therefore be employed with preference in opioid-tolerant patients, as they can provide best possible analgesia to these patients without relying on opioid receptor effects; reliability can be increased by using ultrasound guided techniques and the duration of effect can be extended by infusion of local anesthetics via nerve catheters. However, it is important to realize that regional analgesia techniques, even if they include epidural opioid administration, are insufficient to prevent withdrawal [5]. Even in pain-free patients, the ongoing supplementation with their usual opioids in their usual doses is mandatory. Antihyperalgesic medications
The NMDA receptor antagonist ketamine has been widely used to improve pain relief in acute pain situations [31]. In particular, this medication might be useful in patients who are opioidtolerant. The theoretical considerations in favor of the use of ketamine as an adjunct in opioidtolerant patients have been confirmed in randomized controlled trials, which showed opioid sparing and/or improved analgesia with the use
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of patient-controlled analgesia on the background of a continuous ketamine infusion [32,33]. The α-2-δ subunit modulators, pregabalin and gabapentin, have proven antihyperalgesic properties, for example, in the management of neuropathic pain and fibromyalgia. Premedication with these compounds in the opioid-naive patient results in improved analgesia, reduced opioid consumption and reduced incidence of adverse effects of opioids [34,35]. The substances have also been shown to be effective in reducing opioid-induced hyperalgesia in animal experiments [36] and in a human study [37]. On the basis of this evidence it is reasonable to recommend that gabapentin, or preferably pregabalin because of its superior pharmacok inetics, should be used in the perioperative management of opioid-tolerant patients. An additional advantage might be the reduction of persistent postsurgical pain, as shown in a recent meta-analysis [38]. Prevention of withdrawal Besides the provision of acute pain relief, another important goal in opioid-tolerant patients is the prevention of withdrawal. This is best achieved by continuation of previous opioids in their established long-term dosages. As outlined before, substitution needs to be changed to an equianalgesic dose via the parenteral route if oral intake is not possible in the early postoperative or postinjury period. Furthermore, the use of opioid antagonists, such as naloxone, needs to be avoided under all circumstances [39]. Clonidine can be a useful adjunct in the management of such symptoms [40]. However, clonidine also has adverse effects, such as sedation and hypotension, which need to be considered if it is used to manage withdrawal symptoms. Therefore, prevention of such symptoms by opioid use and titration of opioids against withdrawal symptoms is the better strategy. It is of note that many patients who are abusing opioids are also abusing other substances and can therefore develop withdrawal symptoms, in particular with regard to benzodiazepines and alcohol in the acute phase. In severe cases, these withdrawal symptoms can even be life threatening and require appropriate titration of benzodiazepines, and might again be helped by the use of clonidine. Special considerations in patients on drug
substitution programs
The two most commonly used opioids for the substitution therapy of drug addiction are methadone
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Acute pain management in the opioid-tolerant patient and buprenorphine; only very few countries permit supervised parenteral heroin administration in patients with severe addiction problems. With regard to methadone, there is consensus that the substitution dose of methadone should be continued throughout the acute pain episode. However, as the analgesic effect of methadone is not as long lasting as the substitution effect in many patients, it is standard practice in many services to split the daily methadone dose and provide one-third of the dose every 8 h to achieve best possible analgesic benefit from this medication [41]. If patients have to be kept nil by mouth then methadone needs to be substituted parenterally [20]. The authors’ preferred route is to give a continuous intravenous infusion of 60% of the daily oral dose. There is considerable variability with regard to the attitude towards increasing the substitution dose of methadone in acute pain situations. Some abuse services prefer a clear separation of substitution from analgesia and suggest, therefore, the use of a different opioid to provide analgesia. Other services are more liberal and permit dose increases of the substitution opioid, methadone, to provide improved analgesia in the acute phase. There is no e vidence in favor of one or the other approach. With regard to buprenorphine, the confusion is even more wide ranging. While buprenorphine is pharmacologically characterized as a partial µ-agonist and κ-antagonist, its properties in the clinical setting are similar to other µ-agonist opioids; however, with high opioid-receptor affinity and long duration of binding to the receptor. Therefore, the literature is filled with conflicting recommendations with regard to the continuation or discontinuation of buprenorphine substitution through an acute pain episode. A number of publications quoted in a review that are not based on reliable evidence are concerned about the potential of buprenorphine, with its high receptor affinity and potential antagonistic effects, to block access of full µ-agonists to the opioid receptors and thereby prevent effective analgesia [25]. Therefore, they recommend ceasing buprenorphine in the perioperative period [21]. However, this is not the experience of others [7,42]. Two published case series show that maintaining sublingual buprenorphine substitution throughout an acute pain episode does not preclude opioids from being effective with similar opioid consumption and pain scores in patients on buprenorphine or methadone [43,44]. In line with these observations, we agree to the
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recommendation that buprenorphine maintenance therapy should be continued throughout acute pain episodes [7]. Again, as with methadone, it might be useful to split the daily dose into three doses taken in 8-hourly intervals, as analgesia might not be as long lasting as suppression of opioid withdrawal [39]. We have even successfully increased the buprenorphine maintenance dose in selected patients on high opioid requirements and have not seen impairment of the effect of other opioids used in this setting. Special considerations in patients using
illicit opioids
This rule of maintaining background opioids is most difficult to achieve in patients with a current addiction who are continuing to use illicit opioids, be it heroin or prescription opioids. The issues here are that a stable maintenance dose cannot be easily established, as it depends on the usage pattern of the individual patient and the availability of different purities of heroin respective to different mixtures of prescription opioids. One recommended approach is the use of methadone in doses of 5–10 mg as required to prevent withdrawal symptoms [25]. Management of social issues The management of opioid-tolerant patients cannot exclusively rely on pharmacological intervention. As outlined above, many opioid-tolerant patients, in particular those exhibiting aberrant drug-taking behavior or blatant addiction, suffer from a considerable number of psychiatric comorbidities. In addition, there are often multiple unresolved psychosocial issues ranging from homelessness to ongoing intravenous drug use to abusive behavior. Key issues, particularly in the addicted patients, are that they are often extremely fearful of withdrawal and of unrelieved pain [4]. In addition, these patients often do not cope well with stress and, therefore, show overshooting stress response in the acute painful situation. On the other hand, such patients are often stigmatized by medical and nursing personnel [21]. This is often caused by the difficulties to differentiate drug-seeking behavior from patients’ requests for additional opioids for genuine pain relief; mistaking the latter for addictive behavior has led to the term pseudoaddiction [45]. If patients show behavioral problems, one should always exclude withdrawal [7]. Other issues leading to conflict are manipulation by these patients and a team-splitting
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REVIEW Schug effect, as well as the diversion of opioids provided (e.g., by not taking opioid tablets, but hoarding them) or the illicit use of opioids on the ward (e.g., by injecting oral preparations that were hoarded or supplied by friends, relatives and visitors) [19]. The keys for success are, therefore, the good training of all involved personnel, a team approach, and consistent communication between both the team members themselves, and between the team members and the patient. It is important to outline a treatment plan with thresholds and limits for behavioral aberration [7]. These rules need to be stated clearly and enforced; formulation of these limits in a treatment agreement can be helpful. Special considerations in previously opioid-dependent patients Patients who have successfully participated in drug treatment programs and are now ‘clean’ are no longer on any substitution program. They are extremely fearful of re-exposure to opioids in view of the perceived risk of re-induction of opioid dependence and addiction [25]. These fears need to be addressed in a detailed conversation prior to the need for acute pain relief. In addition, these patients might suffer from a protracted abstinence syndrome that can last for weeks or months, sometimes even years. This syndrome is characterized by a latent neuronal hyperexcitability with increased sensitivity to opioids and, in particular, increased adverse effects [46]. The ideal approach to the provision of acute pain relief in these patients is the use of nonopioid analgesics, appropriate adjuvants and regional anesthesia and analgesia [21]. If this approach is insufficient to provide pain relief then the use of tramadol can be recommended, as even parenteral administration of analgesic doses of tramadol do not lead to recognition of opioid effects in experienced opioid users [47]. However, it will not always be possible to get through a period of severe acute pain with complete avoidance of opioids. It is important to explain to the patient that opioid exposure for pain relief is not necessarily a risk factor for reoccurrence of addiction. On the contrary, there are data to suggest that insufficient pain relief is a more important risk factor here [39]. In the postoperative period, opioids can be titrated; however, more care might be needed with titration than is needed for opioidnaive patients due to the increased sensitivity to opioids in p rotracted abstinence.
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Discharge planning & ongoing management Opioid-tolerant patients who have gone through a period of acute pain, usually as inpatients in a hospital, require careful discharge planning and, in particular, excellent communication with the primary healthcare provider or the drug abuse program the patient is enrolled in [7]. Ideally, chronic pain patients should be discharged on the medication in the doses they were admitted on and this should be communicated with the original prescriber to guarantee ongoing supply. However, this approach might be different if the prescribed opioid amounts seem inappropriate or aberrant drug-taking behavior, including diversion, was identified during the hospital stay. In these cases, the situation needs to be discussed with the patient and the primary prescriber. In extreme cases of diversion or aberrant drug-taking behavior information of the authorities and the involvement of a drug abuse service may be appropriate. Similarly, patients in substitution programs should ideally be discharged on the previously used substitution opioid in the previously established dose and dosing interval. Again, informing the prescriber in the drug abuse program and the dispensing pharmacy are necessary to guarantee ongoing prescribing. Patients who were identified as being opioid tolerant due to illicit opioid use should ideally be referred to a drug abuse service while in hospital. Depending on the legal situation and the infrastructure, such patients who are usually established on an opioid regimen during their hospital stay, commonly using methadone, should sub sequently be transferred into the care of a methadone substitution program. Such approaches are significantly facilitated by the early involvement of a drug abuse service while the patient is in hospital. However, many patients will be discharged from hospital, especially now, with increasing pressures to reduce hospital stay, when their acute pain has not completely resolved. The provision of ongoing analgesia for such an acute pain episode in the out-of-hospital period requires careful planning and good liaison with the primary care providers of the patient. It is recommended that all nonopioid analgesics, and possibly an antihyperalgesic compound, such as pregabalin, is continued upon discharge to achieve maximum opioidsparing effects. Tramadol is possibly a good choice for provision of ongoing analgesia if requirements are not too high [7]. This view is supported by animal studies and review literature, and is also the clinical experience of the author and many
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Acute pain management in the opioid-tolerant patient other clinicians. The risk of diversion is low and the provision of analgesia through nonopioid mechanisms is effective [5]. Nevertheless, there will be patients who require increased opioid provision in the early period after discharge [7]. Here, a number of considerable problems can be encountered. From a medico–legal point of view, the prescription of opioids to patients with an addiction disorder or on a substitution program by doctors other than drug abuse specialists is illegal in a number of countries. Furthermore, a supply of large quantities of immediate-release opioids carries the risk of potential diversion, or deliberate or accidental overdose. Doctors have a poor record of predicting such behavior [48]. Therefore, precautions need to be taken when immediate-release opioids are prescribed for breakthrough pain to such patients. Such precautions include limited supply, possibly daily pick up of limited amounts from a pharmacist, a detailed weaning schedule and discussion with the primary healthcare provider involved [7]. Consideration should be given to increase the dose of the slow-release opioid or even the substitution opioid to provide pain relief, instead of the supply of immediate-release opioids. It is nearly impossible to provide universal rules or standard operating procedures for these situations and an individual decision should be made in close cooperation between the hospital team involved and the providers of healthcare in the out-of-hospital setting [7]. Conclusion & future perspective The number of opioid-tolerant patients requiring acute pain relief is increasing worldwide. Such patients are opioid tolerant due to longterm exposure to opioids for the treatment of chronic cancer and noncancer pain, the illicit intake of opioids or the substitution of such opioids in addiction, and rarely due to short-term management of protracted acute pain episodes. The management of these patients is currently mainly empirical and based on experience, case series and anecdotes, as evidence is lacking. There is consensus that these patients require a multimodal approach with support by a multidisciplinary team to achieve the best results. As a general rule, the previously established opioid therapy and opioid dose should be continued throughout the acute pain episode. Despite this approach, opioid-tolerant patients tend to experience more pain and have higher analgesic requirements than opioid-naive patients.
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The provision of analgesia should rely as much as possible on the use of regional analgesia techniques and systemic multimodal analgesia involving the use of nonopioid analgesics and compounds with antihyperalgesic effects. However, opioid usage cannot always be avoided, and then titration of opioid to effect and adverse effects is even more important than in opioid-naive patients. Opioid-tolerant patients will require higher opioid doses to achieve analgesia. Another important treatment goal is the prevention of withdrawal, which is ideally achieved by maintaining background opioids; rarely, the treatment of withdrawal symptoms with clonidine might be indicated. Throughout the acute pain episode, psychosocial and psychia tric issues, and other comorbidities need to be managed appropriately by involvement of other team members. These patients require careful discharge planning to facilitate the transfer to their primary care provider or drug abuse service. With regard to future directions there is an obvious need for more intense and better performed research into this area. The current lack of evidence in view of the large number of patients concerned is worrying and needs to be addressed. Well-designed randomized trials on the most appropriate measures and the usefulness of antihyperalgesic agents need to be performed. Specifically, the question of how to manage patients on buprenorphine maintenance therapy requires detailed assessment in view of the increasing popularity of this treatment for patients with addiction disorders. Furthermore, it might be that, in the future, the number of opioid-tolerant patients might actually decrease in view of the current change in attitudes towards the management of chronic pain of nonmalignant origin with opioids. After the initial undesirable opiophobia of the 1980s, we are now obviously at a peak of opioid consumption in the developed world, which, particularly in the setting of chronic pain of nonmalignant origin, is not supported by the available evidence [12]. The current development of more conservative treatment guidelines for the management of these patients and the development of risk evaluation and harm-minimization programs in view of the considerable societal problems that have been caused by inappropriate and excessive opioid prescribing might lead to a reduction in the number of patients on opioids long term, in particular those on high doses.
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Financial & competing interests disclosure The Anaesthesiology Unit of the University of Western Australia has received research and travel funding, and speaking and consulting honararia from CSL, Eli Lilly, Gruenenthal, iXBiopharma, Janssen Pharmaceuticals, Mundipharma and Pfizer within the last 2 years. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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