Perioperative management of opioid-tolerant patients

Abstract

Key points•Perioperative pain management for opioid-tolerant patients can be challenging.•Patients taking >100 mg oral morphine equivalent/day have a nine-fold increased risk of inadvertent overdose or adverse events compared to those taking <20 mg/day.•Multi-disciplinary communication, planning, and multi-modal pain management strategies are essential to facilitate the best possible outcomes.•Opioid tolerance and opioid-induced hyperalgesia are complex neurobiological phenomena involving multiple cell signalling pathways.•Patients treated with naltrexone for a substance abuse disorder may have an increased sensitivity to opioid receptor agonists after discontinuing the drug. •Perioperative pain management for opioid-tolerant patients can be challenging.•Patients taking >100 mg oral morphine equivalent/day have a nine-fold increased risk of inadvertent overdose or adverse events compared to those taking <20 mg/day.•Multi-disciplinary communication, planning, and multi-modal pain management strategies are essential to facilitate the best possible outcomes.•Opioid tolerance and opioid-induced hyperalgesia are complex neurobiological phenomena involving multiple cell signalling pathways.•Patients treated with naltrexone for a substance abuse disorder may have an increased sensitivity to opioid receptor agonists after discontinuing the drug. The assessment and treatment of opioid-tolerant patients in the perioperative and postoperative period can be challenging. Acute pain management can often be inadequate due to a number of factors. Compared with opioid-naive patients, opioid-tolerant patients will typically generate a greater workload for medical and nursing staff. Opioid tolerant patients express higher rest and dynamic pain scores, and two to three times greater opioid use via patient-controlled analgesia (PCA). They require more frequent consultations and prescription alterations.1Roberts L Chapter 30: the opioid tolerant patient, including those with a substance abuse disorder.in: Macintyre PE Walker S Rowbotham D Clinical Pain Management, Acute Pain. 2nd Edn. Hodder Arnold, London, UK2008: 539-556Crossref Google Scholar Medical and nursing staff may be unaccustomed to managing such patients and may be apprehensive in prescribing or administering large doses of opioids because of a fear of causing harm. Under-treatment of pain may result in opioid-seeking behaviour with the patient perceived as ‘manipulative’ and ‘non-cooperative’. This can have a negative impact on the doctor–patient relationship and overall patient care. Therefore the pain management plan for opioid tolerant patients requires careful consideration in the perioperative period in order to (i) prevent opioid withdrawal, (ii) provide effective analgesia, and (iii) to ensure continuity of care in the community after discharge from hospital. This review considers the various strategies that can be used in such settings. Opioids are prescribed to treat pain from a variety of causes, including chronic non-cancer pain, cancer pain, acute pain, and as substitution therapy in those with a substance abuse disorder. A discussion regarding the evidence for the use of long-term strong opioids is outside the scope of this article; however, it is important to be aware that treatment with strong opioids is often unwittingly continued, even in the absence of a clinically meaningful benefit. There is evidence to suggest that two-thirds of patients receiving a dose of >120 mg day−1 oral morphine equivalent, or those treated for a duration of >3 months, are likely to continue their medication for years.2Martin BC Fan M-Y Edlund MJ DeVries A Braden JB Sullivan MD Long-term chronic opioid therapy discontinuation rates from the TROUP study.J Gen Intern Med. 2011; 26: 1450-1457Crossref PubMed Scopus (162) Google Scholar The Royal College of Anaesthetists' has recently produced an online resource to increase awareness and support safe opioid prescribing.3Available from https://www.fpm.ac.uk/faculty-of-pain-medicine/opioids-aware (accessed 6 April 2016).Google Scholar In addition, there has been a dramatic increase in opioid prescribing over the last two decades, and this has been paralleled by an increase in adverse events. In the USA, unintentional deaths from drugs more than tripled between 1990 and 2002 and the rate of increase in deaths generally follows the increase in pharmacy sales of strong opioids.4Paulozzi LJ Budnitz DS Xi Y Increasing deaths from opioid analgesics in the United States.Pharmacoepidemiol Drug Saf. 2006; 15: 618-627Crossref PubMed Scopus (559) Google Scholar The risk of an adverse event is higher among patients prescribed >50 mg oral morphine equivalent per day. Patients receiving > 50 or >100 mg day−1 have a 3.7- and 8.9-fold increase in risk of an overdose compared with patients receiving doses <20 mg day−1.5Dunn KM Saunders KW Rutter CM et al.Opioid prescriptions for chronic pain and overdose: a cohort study.Ann Intern Med. 2010; 152: 85-92Crossref PubMed Scopus (1001) Google Scholar It is therefore of paramount importance to formulate and communicate a plan for onward-care after discharge from hospital. This may typically involve a discussion with the patient's GP and a carefully documented discharge letter highlighting the importance of reducing and stopping treatment if it is ineffective or no longer required. Some patients may already have agreed plans in place with their GP (e.g. weekly or daily prescription). Either way, a discussion with the patient, GP, and pharmacist can encourage a consistent and safer system of working. There is no doubt that assessment of pain can be challenging and opioid tolerant patients consistently report higher pain scores. When assessing the overall effectiveness of pain management, it is important to consider other important factors. These include the presence of opioid-related side-effects, signs of opioid withdrawal, patient expectations, patient satisfaction, mood, and levels of physical function (e.g. ability to cough, deep breathe, and engage with physiotherapists and other services). The early identification of complex patients by surgeons and preoperative assessment staff is highly recommended and can facilitate forward planning and ample time to involve the experience of others (e.g. anaesthetists, pain specialists, psychologist, GP, occupational therapists and physiotherapists etc). It is important to adhere to a clear and well-documented multi-disciplinary management plan that has been created with the involvement of the patient. Opioid-sparing techniques may be of particular importance in patients taking strong opioids. •Regularly prescribed paracetamol, non-steroidal anti-inflammatory drugs, or COX-2s should be used unless contraindicated.6Macintyre PE Schug SA Scott DA Visser EJ Walker SM APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain MedicineAcute Pain Management: Scientific Evidence. 3rd edition. ANZCA & FPM, Melbourne2010: 426-431Google Scholar–9Huxtable CA Roberts LJ Somogyi AA MacIntyre PE Acute pain management in opioid-tolerant patients: a growing challenge.Anaesth Intensive Care. 2011; 39: 804-823Crossref PubMed Google Scholar•The use of local anaesthetic techniques including wound infiltration, regional, or neuroaxial block should be used where possible to improve postoperative analgesia and decrease immediate-release (IR) opioid requirement. Local anaesthetic catheters can prolong the benefits of regional anaesthesia well into the postoperative period.6Macintyre PE Schug SA Scott DA Visser EJ Walker SM APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain MedicineAcute Pain Management: Scientific Evidence. 3rd edition. ANZCA & FPM, Melbourne2010: 426-431Google Scholar–9Huxtable CA Roberts LJ Somogyi AA MacIntyre PE Acute pain management in opioid-tolerant patients: a growing challenge.Anaesth Intensive Care. 2011; 39: 804-823Crossref PubMed Google Scholar•Ketamine is recommended in the acute pain management of opioid-tolerant patients as it has been shown to reduce postoperative opioid use and pain scores. Activation of the N-methyl-d-aspartate (NMDA) receptor is believed to be one of the mechanisms for the development of opioid tolerance and opioid-induced hyperalgesia (OIH). Ketamine is a non-competitive antagonist of the NMDA receptor and can attenuate both of these phenomena. Ketamine administered in a low dose as a continuous i.v. or subcutaneous infusion for 1–3 days can be a useful adjunct for opioid-tolerant patients.6Macintyre PE Schug SA Scott DA Visser EJ Walker SM APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain MedicineAcute Pain Management: Scientific Evidence. 3rd edition. ANZCA & FPM, Melbourne2010: 426-431Google Scholar, 7Macintyre PE Schug SA Scott DA Visser EJ Walker SM APM: SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain MedicineAcute Pain Management: Scientific Evidence. 3rd edition. ANZCA & FPM, Melbourne2010: 433-437Google Scholar, 8Ramaswamy S Wilson J Colvin L Non-opioid-based adjuvant analgesia in perioperative care.Contin Educ Anaesth Crit Care Pain. 2013; 13: 152-157Crossref Scopus (41) Google Scholar There are a number of dosing regimes available; however, the authors recommend a starting dose of 100–200 mg 24 h−1, using a mixture of 200 mg ketamine and 5 mg midazolam made up to a total volume of 48 ml with normal saline and a rate of infusion of 1–2 ml h−1.•The use of gabapentinoids (e.g. gabapentin/pregabalin) in acute pain has become more prevalent, particularly in enhanced recovery protocols. Initial studies indicated improved postoperative pain relief and reduced opioid use, but this was traded against an increased risk of sedation. Lunn and colleagues10Lunn TH Husted H Laursen MB Hansen LT Kehlet H Analgesic and sedative effects of perioperative gabapentin in total knee arthroplasty: a randomized, double-blind, placebo-controlled dose-finding study.Pain. 2015; 156: 2438-2448Crossref PubMed Scopus (66) Google Scholar published a study in 2015 of gabapentin as part of an enhanced recovery protocol for total knee arthroplasty. Gabapentin conferred no benefit when used with other multimodal analgesia and produced dose-related side-effects that compromised recovery in some patients. The benefit of gabapentinoids in the treatment of opioid-naïve patients for routine acute pain management is uncertain. However, gabapentinoids may have a role in opioid-tolerant patients as an opioid-sparing adjunct. The authors recommend their use in patients who, despite maximizing other opioid-sparing techniques and using appropriate doses of opioids, still have poorly managed pain. There is little clinical evidence to support their use in this group of patients or to guide their dosing regime. The authors use postoperative doses similar to that for the initial management of neuropathic pain such as gabapaentin 100–300 mg t.d.s. and pregabalin 50–75 mg b.d., titrated according to efficacy and side-effects.1Roberts L Chapter 30: the opioid tolerant patient, including those with a substance abuse disorder.in: Macintyre PE Walker S Rowbotham D Clinical Pain Management, Acute Pain. 2nd Edn. Hodder Arnold, London, UK2008: 539-556Crossref Google Scholar,9Huxtable CA Roberts LJ Somogyi AA MacIntyre PE Acute pain management in opioid-tolerant patients: a growing challenge.Anaesth Intensive Care. 2011; 39: 804-823Crossref PubMed Google Scholar Again, a mechanism should be in place to ensure a review of medication in the community as gabapentinoids are also known to be abused.•The use of i.v. lidocaine infusions can be useful in some situations and is the subject of a review11Eipe N Gupta S Penning J Intravenous lidocaine for acute pain: an evidence-based clinical update.BJA Education. 2016; 16: 292-298Crossref Scopus (104) Google Scholar in this journal. Withdrawal symptoms occur if a drug is suddenly stopped, reversed, reduced too quickly, or fails to reach its intended site of action. It is generally recommended that the patient's baseline opioid (usually a sustained-release form) is continued in the postoperative period and that acute post-surgical pain is managed with the addition of appropriate doses of IR opioids. We would recommend continuing transdermal opioids at their baseline dose, although caution must be taken with the positioning of the patch. Direct heat applied to the patch, for example, via perioperative warming devices may enhance drug administration, whereas the use of a patch over an area of poor-perfusion or reduced temperature can reduce drug delivery.12Margetts L Sawyer S Transdermal drug delivery: principles and opioid therapy.Contin Educ Anaesth Crit Care Pain. 2007; 7: 171-176Crossref Scopus (99) Google Scholar The use of a buprenorphine patch (up to 70 μg h−1) is unlikely to interfere with the use of full opioid agonists for acute pain management and these should also be continued in the perioperative period.1Roberts L Chapter 30: the opioid tolerant patient, including those with a substance abuse disorder.in: Macintyre PE Walker S Rowbotham D Clinical Pain Management, Acute Pain. 2nd Edn. Hodder Arnold, London, UK2008: 539-556Crossref Google Scholar However, the management of patients taking high-dose sublingual (SL) buprenorphine as a substitution therapy for drug addiction can be problematic, and is discussed later. It is important to remember that parenteral replacement may be needed if a patient taking oral opioids is unable to take medication orally or is not absorbing from the gut (Table 1).Table 1Converting to an equivalent i.v. dose of morphine •An opioid-tolerant patient taking 200 mg of sustained-release morphine twice daily requires an emergency laparotomy and is expected to be nil by mouth postoperatively.•To prevent withdrawal, maintain the usual oral 24 h opioid dose of 400 mg•Convert the dose of oral morphine to i.v. morphine. Ratio between 3 and 2:1•Using a 3:1 conversion ratio•Total i.v. dose over 24 h=133 mg•Background infusion (133 mg 24 h−1)=5.5 mg h−1•Bolus dose: start at 50% of the hourly background rate=2.5–3 mg (with 5 min lockout) Open table in a new tab In the postoperative period, opioid-tolerant patients may require a greater amount of IR oral opioids than is usually expected. Traditionally, the ‘as required’ (p.r.n.) dose is calculated based on the cumulative oral opioid dose given in the preceding 24 h with one-sixth of the total dose prescribed 4 hourly. Nevertheless, the dose of IR opioid required for analgesia may not correlate so easily, and starting with standard doses may be appropriate with regular assessment and titration depending on patient response. I.V. PCA is in widespread use for the management of acute pain. It allows individual dose titration and reduces workload for staff. It can be difficult to identify the optimal starting regime in opioid-tolerant patients, but one method is to base the size of the bolus dose on the patient's usual 24 h opioid requirement (Table 1). Switching from one opioid to another (opioid rotation) is a common practice in chronic pain and cancer pain management. It is a useful option if patients have developed intolerable side-effects or inadequate analgesia, despite escalating doses. Although patients also develop tolerance to side-effects (e.g. itching, nausea, and sedation), the rate of development is non-uniform and unpredictable. If a patient develops tolerance to analgesia at a greater rate than to side-effects, they are often unable to tolerate the increased doses required for analgesia. Rotation can lead to both a reduction in side-effects and an improvement in pain relief because an individual may respond differently to an alternative opioid due to the phenomenon of incomplete cross-tolerance. Cross-tolerance is the observation that exposure to a particular drug (e.g. opioid) results in tolerance to the effects of structurally similar drugs in the same class (e.g. other opioids). When cross-tolerance is incomplete, patients may not have tolerance to the alternative drug. Equianalgesic tables (Fig. 1) are commonly used to help calculate the equivalent dose of an alternative opioid, but should be used cautiously. They are based on small studies, single doses, and healthy opioid-naïve volunteers. They therefore do not reflect complex and heterogeneous clinical situations.13Natusch D Equianalgesic doses of opioids—their use in clinical practice.Br J Pain. 2012; 6: 43-46Crossref PubMed Google Scholar When performing an opioid rotation, it is recommended to reduce the calculated equianalgesic dose by 30–50% because of the possibility of incomplete cross-tolerance. Patients can use additional IR opioids if necessary. As an example of an opioid rotation in the perioperative setting, consider a patient whom is usually prescribed methadone, and will be nil by mouth after an emergency laparotomy. It is important to replace the background opioid requirement to prevent opioid withdrawal, and this might be achieved via the use of a fentanyl or morphine PCA (Table 2).Table 2Opioid rotation from oral methadone to i.v. morphine •An emergency laparotomy is required in a patient taking 100 mg of oral methadone and whom will be nil by mouth after operation•As the patient is unable to take oral methadone, this is converted to a suitable i.v. dose to prevent withdrawal•Conversion ratio for oral methadone to oral morphine 1:2 or 3•Using a 1:3 ratio 100 mg of oral methadone is equivalent to 300 mg of oral morphine•300 mg of oral morphine is equivalent to a 100 mg of i.v. morphine•Due to incomplete cross-tolerance between opioids, a 50% reduction in the calculated equianalgesic dose is recommended•The dose of i.v. morphine required to prevent withdrawal over 24 h is 50 mg•This can be provided via PCA with either (a)an increased bolus dose of between 1.5 and 2 mg or(b)a standard PCA bolus of 1 mg but with a background infusion of 2 mg h−1 Open table in a new tab Patients will need to be converted back to oral medication as their clinical situation allows. A typical strategy for returning to oral medication is to identify the i.v. opioid consumption in the previous 24 h and convert this to an equivalent oral dose. Fifty per cent of this oral equivalent dose is then given in a sustained-release form, and one-sixth of the equivalent dose is prescribed as an IR preparation every 4 h (Table 3).Table 3Converting from i.v. to oral opioid(i) 60 mg i.v. morphine 24 h−1=120–180 mg oral morphine(ii) 50% of this dose=60–90 mg/day and therefore=30–45 mg morphine sulphate (MST) b.d.(iii) PRN=1/6 of 120–180 mg=20–30 mg p.r.n. 4 hourly Open table in a new tab Opioid tolerance (for definitions, see Table 4) is frequently encountered in patients taking long-term opioids. In order to improve analgesia either an increase in the opioid dose or an opioid rotation could be considered. On the contrary, OIH is a paradoxical phenomenon whereby an opioid can induce a pronociceptive state in the central nervous system. OIH was first observed in patients taking methadone for opioid addiction. The underlying mechanism is complex but likely to involve a combination of glial cell activation, NMDA receptor activation, glutaminergic activation, and alterations in opioid intracellular signalling.14Lee M Silverman SM Hansen H Patel VB Manchikanti L A comprehensive review of opioid-induced hyperalgesia.Pain Physician. 2011; 14: 145-161Crossref PubMed Google Scholar As a result, the treatment of OIH necessitates an opioid dose reduction. This can be a difficult concept to understand for a patient who is in pain, as well as for their doctor. Nevertheless, it is often difficult to clinically distinguish between opioid tolerance, OIH, and progression of the underlying disease process. Importantly, patients with OIH may report more diffuse and widespread pain and ‘sensitivity’ which does not respond to an increase in the dose of opioid.Table 4DefinitionsTolerance •Predictable and physiological•Increased dose required for the same effectPhysical dependence •Predicable and physiological•Stop, reverse, reduce = withdrawal syndromeAddiction •Unpredictable effect of drug (a disease)•Aberrant drug-seeking/drug-taking behaviour•Despite risks of physical, social, and psychological harmPseudo-addiction •Drug seeking due to under-treatment of pain•Resolves when pain relief adequate•Based on one 1989 case report,15Weissman DE Haddox Jd Opioid pseudoaddiction - an iatrogenic syndrome.Pain. 1989; 36: 363-366Abstract Full Text PDF PubMed Scopus (503) Google Scholar and definition never subjected to serious studyOpioid-induced hyperalgesia •A state of nociceptive sensitization secondary to exposure to opioids. Often more diffuse and widespread pattern of pain Open table in a new tab It was previously thought that OIH only occurred in patients on long-term opioids, but both tolerance and OIH have been associated with short-term use of high potency opioids, for example, remifentanil. However, this association has not been fully established and studies are conflicting.1Roberts L Chapter 30: the opioid tolerant patient, including those with a substance abuse disorder.in: Macintyre PE Walker S Rowbotham D Clinical Pain Management, Acute Pain. 2nd Edn. Hodder Arnold, London, UK2008: 539-556Crossref Google Scholar The prevalence of problem drug use is ∼1 in 100 people between the ages of 15–64, and the use of i.v. drugs is ∼1 in 300.15Weissman DE Haddox Jd Opioid pseudoaddiction - an iatrogenic syndrome.Pain. 1989; 36: 363-366Abstract Full Text PDF PubMed Scopus (503) Google Scholar Substitution therapy aims to reduce harm from problem drug use, provide stability, prevent withdrawal, and reduce preoccupation and craving. Methadone is typically started (specialist only) at a dose of between 10 and 40 mg, and increased in 10 mg increments (max 30 mg week−1) to a typical maintenance dose of between 60 and 120 mg day−1. Buprenorphine as a maintenance therapy is typically administered as an SL dose between 0.8 and 4 mg (max 32 mg) with typical maintenance doses of between 12 and 24 mg.15Weissman DE Haddox Jd Opioid pseudoaddiction - an iatrogenic syndrome.Pain. 1989; 36: 363-366Abstract Full Text PDF PubMed Scopus (503) Google Scholar Methadone is a μ-agonist as well as an NMDA-antagonist and monoamine reuptake inhibitor. It is metabolized in the liver to inactive metabolites by CYP3A4, which is saturated at low concentrations, and itself also weakly inhibited by methadone. Patients who are receiving methadone maintenance therapy should be managed as any other opioid-tolerant patient. If able, they should continue taking their usual oral methadone in the perioperative and postoperative periods. Additional IR opioids should be used to manage acute pain if appropriate. If patients need to be nil by mouth or there is concern about gastrointestinal absorption, there should be consideration of a rotation to an i.v. fentanyl or morphine PCA to prevent withdrawal and provide analgesia (Table 4). Buprenorphine is a partial agonist at μ-receptors, and an antagonist at κ and δ receptors. It has a high affinity for opioid receptors, and dissociates slowly resulting in an extended duration of action. It is used in addiction medicine to suppress opioid withdrawal and craving for 24–48 h, and is less sedating and euphoric. There is a theoretical concern that the use of high-dose SL buprenorphine will antagonize the effect of a full agonist, thereby leading to either opioid withdrawal (if the patient is already taking high-dose full agonists) or analgesic failure. There are very few reports describing perioperative pain management of patients administered high-dose SL buprenorphine. Strategies in this situation have included continuing the usual dose of buprenorphine and either (i) providing additional full opioid agonists or (ii) prescribing supplemental doses of buprenorphine. An alternative strategy involves rotating to a full agonist before surgery such as methadone. In one series, five patients having seven major operations were taking 2–24 mg buprenorphine per day. Pain control was reported to be adequate with oral or i.v. full agonists.16Available from http://www.nice.org.uk/guidance/ta114 (accessed 29 October 2015).Google Scholar In a randomized controlled trial comparing PCA morphine, with or without the addition of buprenorphine, there was no detrimental effect on analgesia with the addition of buprenorphine.17Kornfeld H Manfredi L Effectiveness of full agonist opioids in patients stabilized on buprenorphine undergoing major surgery: a case series.Am J Ther. 2010; 17: 523-528Crossref PubMed Scopus (57) Google Scholar Successful postoperative pain management has been reported with additional doses of buprenorphine. In one case report, a baseline of 24/6 mg buprenorphine/naloxone was supplemented by additional 2/0.5 mg as required, reaching a maximum daily dose of 72/18 mg. The patient was able to self-titrate back to the original starting dose by 11 days.18Oifa S Sydoruk T White I et al.Effects of intravenous patient-controlled analgesia with buprenorphine and morphine alone and in combination during the first 12 postoperative hours: a randomized, double-blind, four-arm trial in adults undergoing abdominal surgery.Clin Ther. 2009; 31: 527-541Abstract Full Text PDF PubMed Scopus (50) Google Scholar The authors currently recommend continuing the patients usual dose of SL buprenorphine, maximizing the use of opioid-sparing adjuncts, and using conventional full opioid agonists to treat acute pain. The doses of IR opioid required for analgesia may be appreciably higher than one would expect for other opioid-tolerant patients and in view of this, it may be advisable to monitor the patient in a high dependency environment. Naltrexone is primarily used in patients whom are highly motivated to remain abstinent from alcohol or a substance abuse disorder. It is a long-acting competitive opioid antagonist with a duration of action of ∼48–72 h. Chronic use results in increased sensitivity to morphine-induced analgesia and a doubling of brain μ- and δ-opioid receptors, which may return to baseline in ∼6 days post-treatment.19Book SW Myrick H Malcolm R Strain EC Buprenorphine for postoperative pain following general surgery in a buprenorphine-maintained patient.Am J Psychiatry. 2007; 164: 979Crossref PubMed Google Scholar It is recommended to stop naltrexone 72 h prior to surgery, and it is important to note that although patients may be resistant to opioids while taking naltrexone, they may then become extremely opioid sensitive once stopping it. It is therefore imperative to maximize opioid-sparing strategies (e.g. regional anaesthesia), and consider managing the patient in a high dependency setting in the postoperative period, to ensure appropriate monitoring of treatment. The number of patients who are receiving long-term opioid therapy has increased dramatically, and the provision of analgesia in the perioperative period can be challenging. Fundamental aspects of management include continuing baseline opioid requirements and maximizing other opioid-sparing techniques. Patients on substitution therapy for substance abuse disorders can pose unique challenges. A multi-disciplinary and multimodal approach to analgesia is essential, as well as ensuring there is a continuing plan in place for onward care in the community, to appropriately manage strong opioids or other adjuvants analgesics after discharge.