European clinical practice recommendations on opioids for chronic noncancer pain – Part 2: Special situations*

Eur J Pain. 2021;25:969–985. | 969 wileyonlinelibrary.com/journal/ejp Received: 12 October 2020 | Accepted: 5 February 2021 DOI: 10.1002/ejp.1744 POSITION PAPER European clinical practice recommendations on opioids for chronic noncancer pain – Part 2: Special situations* NevenkaKrčevski Škvarč1 | BartMorlion2 | Kevin E.Vowles3 | KirstyBannister4 | EricBuchsner5 | RobertoCasale6 | Jean- FrançoisChenot7 | GillianChumbley8 | Asbjørn MohrDrewes9 | GeertDom10 | LiisaJutila11 | TonyO‘Brien12 | EstherPogatzki- Zahn13 | MartinRakusa14 | CarmenSuarez– Serrano15 | ThomasTölle16 | WinfriedHäuser17,18 1Department of Anesthesiology, Intensive Care and Pain Treatment, Faculty of Medicine of University Maribor, Maribor, Slovenia 2Center for Algology & Pain Management, University Hospitals Leuven, Leuven, Belgium 3School of Psychology, Queen's University Belfast, Belfast, UK 4Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK 5Pain Management and Neuromodulation Centre EHC Hospital, Morges, Switzerland 6Neurorehabilitation Unit, Department of Rehabilitation, HABILITA, Bergamo, Italy 7Department of General Practice, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany 8Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK 9Mech- Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark 10Collaborative Antwerp Psychiatric Research Institute (CAPRI), Antwerp University (UA), Antwerp, Belgium 11Pain Alliance Europe, Finland 12College of Medicine & Health, University College Cork, Cork, Republic of Ireland 13Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster UKM, Munster, Germany 14Department of Neurology, University Medical Centre Maribor, Maribor, Slovenia 15Department of Physiotherapy, University of Sevilla, Sevilla, Spain 16Department of Neurology, Techhnische Universität München, München, Germany 17Department Internal Medicine 1, Saarbrücken, Germany 18Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München, Munich, Germany This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made. © 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®. *Developed by European Pain Federation (EFIC). Endorsed by European Academy of Neurology (EAN), European Federation of Addiction Societies (EUFAS), European Federation of Psychologists’ Associations (EFPA), European Headache Federation (EHF), European Psychiatric Association (EPA), European Region - World Confederation of Physical Therapy (ERWCPT), European Society of Anaesthesiology and Intensive Care (ESAIC), European Society of Physical and Rehabilitation Medicine (ESPRM), European Society of Regional Anaesthesia & Pain Therapy (ESRA) and Pain Alliance Europe (PAE). Correspondence Winfried Häuser, Internal Medicine 1, Klinikum Saarbrücken, D- 66119 Saarbrücken, Germany. Email: [email protected] Abstract Background: Opioid use for chronic noncancer pain (CNCP) is under debate. In the absence of pan- European guidance on this issue, a position paper was commissioned by the European Pain Federation (EFIC). 970 | KRČEVSKI ŠKVARČ et al. 1 | INTRODUCTION Therapy with opioids for chronic noncancer pain (CNCP) is associated with clinically meaningful side effects and risks. In randomized controlled trials, the dropout rates due to adverse events are higher than with placebo (Petzke etal.,2020; Sommer et al., 2020; Welsch etal., 2020). The most frequent side effects leading to discontinuation of opioids in RCTs for CNCP are gastrointestinal (e.g., nausea, constipation) and neurological (e.g. somnolence) side effects (Kalso etal.,2004). In observational studies, an increased risk of severe harms such as hypogonadism, opioiduse disorder or sleeprelated breathing disorders have been described (Chou etal.,2020). The use of opioids for CNCP in special situations such as in children and adolescents (Cooper et al., 2017) is under debate. In part I of the European Clinical Practice Recommendations for appropriate use of opioids for CNCP (Häuser etal.,2021), we have highlighted the need to monitor people prescribed with opioids for CNCP regularly to detect side effects of treatment. In part II we give guidance for the use of opioids in special clinical populations (e.g. children, pregnant women) and situations (e.g. liver and renal failure) and for the prevention and management of side effects. 2 | METHODS The methods have been outlined in part I of the European Clinical Practice Recommendations for appropriate use of opioids for CNCP (Häuser etal.,2021). In short, the clinical practice recommendations were developed by eight scientific societies and one patient selfhelp organization under the coordination of EFIC. A systematic literature search in MEDLINE (up until January 2020) was performed.Two categories of guidance are given: Evidencebased recommendations (supported by evidence from systematic reviews of randomized controlled trials or of observational studies) and Good Clinical Practice (GCP) statements (supported either by indirect evidence or by caseseries, casecontrol studies and clinical experience). The GRADE system was applied to move from evidence to Methods: The clinical practice recommendations were developed by eight scientific societies and one patient selfhelp organization under the coordination of EFIC. A systematic literature search in MEDLINE (up until January 2020) was performed.Two categories of guidance are given: Evidencebased recommendations (supported by evidence from systematic reviews of randomized controlled trials or of observational studies) and Good Clinical Practice (GCP) statements (supported either by indirect evidence or by caseseries, case– control studies and clinical experience). The GRADE system was applied to move from evidence to recommendations. The recommendations and GCP statements were developed by a multiprofessional task force (including nursing, service users, physicians, physiotherapy and psychology) andformal multistep procedures to reach a set of consensus recommendations. The clinical practice recommendations were reviewed by five external reviewers from North America and Europe and were also posted for public comment. Results: The European Clinical Practice Recommendations give guidance for combination with other medications, the management of frequent (e.g. nausea, constipation) and rare (e.g. hyperalgesia) side effects, for special clinical populations (e.g. children and adolescents, pregnancy) and for special situations (e.g. liver cirrhosis). Conclusion: If a trial with opioids for chronic noncancer pain is conducted, detailed knowledge and experience are needed to adapt the opioid treatment to a special patient group and/or clinical situation and to manage side effects effectively. Significance: If a trial with opioids for chronic noncancer pain is conducted, detailed knowledge and experience are needed to adapt the opioid treatment to a special patient group and/or clinical situation and to manage side effects effectively. A collaboration of medical specialties and of all health care professionals is needed for some special populations and clinical situations. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 971 KRČEVSKI ŠKVARČ et al. recommendations. The recommendations and GCP statements were developed by a multiprofessional task force (including nursing, service users, physicians, physiotherapy and psychology) andformal multistep procedures to reach a set of consensus recommendations. The clinical practice recommendations were reviewed by five external reviewers from North America and Europe and were also posted for public comment. 3 | RESULTS 3.1 | Part 3: Special situations 3.1.1 | Differential indication of different opioids 3.1.1.1 Transdermal systems. Transdermal systems with opioids should not be considered if there are clinically meaningful day and night variations in pain intensity. Good clinical practice statement. Consensus (12/13; 7/8). Comment: Transdermal opioid formulations can be usedin patients with gastrointestinal disorders despite fluctuating pain intensity whenabsorption of oral formulations are considered troublesome. 3.1.1.2 Shortversus long acting oral opioids. The decision to prescribe immediaterelease- or extended release (longacting) opioids can be considered based on the individual situation and clinical presentation (e.g., variability in time of pain). Good clinical practice statement. Consensus (13/14; 8/9). Comment: The Canadian guidelines recommend that clinicians can prescribe extended release opioids in patients with continuous pain (including pain at rest), both for comfort and simplicity of treatment. Activityrelated pain may not require extended release release treatment and opioid therapy may be initiated with immediate - release alone (Busse et al., 2017). The CDC guidelines recommend starting opioid therapy with immediaterelease opioids instead of extendedrelease/longacting opioids (Dowell etal.2016). The German guidelines recommend the use of longacting opioids by a fixed schedule (Häuser etal.,2020). The French guideline does not comment on this topic (Moisset & Martinez, 2016). A systematic review included 16 randomized trials and eight observational studies comparing long- and shortacting opioids. None of the randomized trials was rated as good quality. The authors concluded that there was insufficient evidence to determine whether longacting opioids are more effective or safer than shortacting opioids (Chou etal.,2003). North American studies found signals that adverse events (e.g. unintentional overdose deaths, opioid control, concern of the patient) are more frequent with longacting rather than shortacting opioids (Sullivan,2014). There was no evidence to support that longacting opioids were superior or inferior to shortacting ones in improving functional outcomes, reducing side effects or addiction. 3.1.1.3 Medication ondemand with immediate release opioids in the adjustment phase. Demand medication with immediate release oral opioids can be considered to determine the optimal dose. Good clinical practice statement. Strong Consensus (15/15; 10/10). 3.1.1.4 Ultrashort acting buccal or nasal opioids. Ultrashort acting buccal or nasal opioids should not be considered for use as rescue medication. Good clinical practice statement. Consensus (12/15; 9/10). Comment: Based on clinical experience, the TF perceived a relevant risk of misuse of ultrashort acting opioids for CNCP. In addition, ultrashort acting buccal or nasal opioids are not approved for CNCP. In special circumstances (e.g., patients with gastrointestinal disorders with fluctuating absorption, vomiting) these substances can be considered. 3.1.2 | Combination with other centrally acting medications 3.1.2.1 Combination with benzodiazepines. We suggest not prescribing opioids and benzodiazepines simultaneously. Weak recommendation. Consensus (15/16; 10/11) Rationale: Benzodiazepines and opioids both cause central nervous system depression and can decrease respiratory drive. Concurrent use is likely to put patients at greater risk for a potentially fatal overdose. Observational studies conducted in North America and Europe have demonstrated that concurrent benzodiazepine and opioid use increases the frequency of adverse events (Dowell etal.,2016). Evidence summary PICO: Population: Patients with chronic noncancer pain with opioid therapy, Intervention: Opioids and tranquilizer. Comparator: Opioids. Outcome: Serious adverse events. Emergency room admissions for overdoses: In a US study of 315,428 privately insured persons aged 18– 64years (excluding past or present cancers) in the years 2001– 2013, the combined use of opioids (at least one dose) and tranquilizers compared to monolong- term therapy with opioids was associated with an increased risk of presentation in the emergency room or inpatient admission due to overdoses [adjusted odds ratio (OR) 1.81 (1.67 – 1.96) (Sun etal.,2017). Abuse and dependence: In a retrospective crosssectional study in 2014 including 69 German statutory health insurance funds with a total of 4,028,618 insured persons on LTOT for CNCP, hospital stays were associated with diagnoses of mental and behavioural disorders due to alcohol, opioids, tranquilizers and multiple substance use as well as intoxication by narcotics with the prescription of tranquilizers [OR 3.63; (3.03; 4.36)] (Häuser etal.2018). 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 972 | KRČEVSKI ŠKVARČ et al. Deaths: In a US study with former members of the armed forces in the years 2004– 2009, 2,400 deaths were described in connection with opioid medication and tranquilizers. The hazard ratio (HR) was 3.86 (3.49; 4.26, no absolute figures were given, Park etal.,2015). In a prospective observational study with a 1- year followup with US American senior citizens' home residents, 478 deaths related to overdose (0.022% per year for 2,182,374 people) were found. Death rates due to overdoses were 10 times higher (7.0 [6.3, 7.8] per 10,000 personyears) under a combination therapy of opioids and benzodiazepines than under opioids alone (0.7 [0.6, 0.9] per 10,000 personyears, no absolute numbers given) (Dasgupta etal.,2016). In a study in US veterans, the association between guidelineequitable longterm opioid therapy and 1- year mortality was investigated. The mortality rate was elevated when comedicated with opioids and benzodiazepines (HR 1.39 [1.12, 1.66]). A decrease in mortality was found with concomitant psychotherapy (HR 0.62; [0.51, 0.71]) and physical rehabilitation (HR 0.81 [0.67, 0.98]). A decrease in mortality was also found in cases of substance dependence when addiction therapy was used (HR 0.47 [0.32, 0.68]) (Gaither etal.,2016). In a retrospective US cohort study, the risk of overdose death was particularly high for opioids combined with benzodiazepines and skeletal muscle relaxants (aHR, 12.6; 95% CI: 8.9, 17.9). Even at opioid doses 1– 19mg MEQ/d, patients using sedativehypnotics concurrently had 5.6 times the risk than patients without sedativehypnotics (aHR, 5.6; 95% CI: 1.6, 19.3) (Garg etal.,2017). The significance of the studies is limited by the retrospective nature of most studies and possible conflicting variables (e.g., confounding by indication). In patients who are already treated by opioids combined with tranquilizers, a careful tapering should be conducted. 3.1.2.2 Combination with gabapentinoids. We suggest that care be exercised in relation to combination therapy with opioids and gabapentinoids due to potential risks of respiratory depression and opioid overdose. Weak recommendation. Consensus (13/14;8/9). Rationale: Gabapentinoids and opioids both cause central nervous system depression and may decrease respiratory drive (McAnally et al., 2020). Concurrent use is likely to put patients at greater risk for a potentially fatal overdose. Observational studies conducted in Canada have found increased mortality when opioids were combined with gabapentinoids compared to opioids alone. Evidence summary PICO: Population: Patients with chronic noncancer pain with opioid therapy Intervention: Opioids and Gabapentinoids. Comparator: Opioids. Outcome: Serious adverse events. There is only one RCT in CNCP which demonstrated the superiority of a combination of morphine plus gabapentin versus single therapy for painful diabetic neuropathy or postherpetic neuralgia (Gilron etal.,2005). A systematic review identified only seven eligible RCTs with different combinations for neuropathic pain. Combination therapy received an inconclusive GRADE recommendation due to conflicting findings (Finnerup etal.,2015). However, the combination of opioids with other classes of analgesics are frequently used in routine clinical care. The Canadian Health Authority, Health Canada, in a communication dated 17 September 2019, drew the attention of Canadian citizens to the increased risk of opioid overdoses and other serious side effects when taking pregabalin or gabapentin at the same time (Health Canada,2019). In a Canadian populationbased nested case– control study (case– control study in which cases and controls were drawn from the population of a cohort study), which considered data from 1997 to 2013, the mortality of patients on combination therapy of opioids and gabapentin was increased compared with opioid monotherapy: [OR 1.99 (1.61– 2.47)] (Gomes etal.2017]. The US Food and Drug Administration (FDA), in a communication of 19 December 2019, pointed out the risk of respiratory depression and fatal opioid overdose when opioids are combined with pregabalin and gabapentin (Food & Drug Admininstration,2019). The British Medicines and Healthcare products Regulatory Agency recommended to carefully observe patients for signs of CNS depression when prescribing gabapentin in patients who require concomitant treatment with opioid medicines (Medicines & Healthcare products Regulatory Agency,2017). Reports from North America need to be scrutinized in light of the opioid epidemic. In addition, the significance of the studies is limited by the retrospective nature and possible conflicting variables (e.g., confounding by indication). 3.1.2.3 Serotonin syndrome. Physicians prescribing opioids should consider paying special attention to the occurrence of a serotoninsyndrome if fentanyl, methadone, oxycodone, tapentadol and tramadol are combined with medications with other serotonergic medication. Good clinical practice statement. Strong Consensus (15/15; 10/10). Comment: Symptoms can range from mild to fatal and classically include altered mental status, autonomic dysfunction and neuromuscular excitation. Several criteria exist for making this clinical diagnosis, but the Hunter criteria are generally accepted as the most accurate. The diagnosis can be made in patients with a history of exposure to a serotonergic drug plus one or more of the following: spontaneous clonus, inducible clonus with agitation and diaphoresis, ocular clonus with agitation and diaphoresis, tremor and hyperreflexia, hypertonia, temperature over 38°C with ocular or inducible clonus (Simon & Keenaghan,2019). 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 973 KRČEVSKI ŠKVARČ et al. Serotonergic medications include SSRI, SNRI, tricyclic agents, MAO- inhibitors, NaSSA (Mirtazapine), St. John's word, L- Tryptophan, Lithium, triptanes (Baldo,2018). 3.1.2.4 Anticholinergic syndrome. Physicians prescribing opioids should pay special attention to the occurrence of anticholinergic syndrome if opioids are combined with antidepressants and neuroleptics. Good clinical practice statement. Strong Consensus (15/15; 10/10). Comment Peripheral anticholinergic syndrome: constipation, urinary retention, tachycardia, hypertension, mydriasis, dry skin and mucous membranes. Central anticholinergic syndrome: decrease in vigilance, aggressiveness, agitation, hallucinations, coma, dizziness and dysarthria. Older patients in particular are sensitive to anticholinergic side effects. Anticholinergic medications include: Antihistamines (Diphenhydramine, Doxylamine, Promethazine, Chlorpheniramine, Cyproheptadine); antitussives (Dextromethorphan); antidepressants (tricyclic antidepressants Amitriptyline, Imipramine, Doxepin); antipsychotics (Chlorpromazine, Droperidol, Haloperidol, Quetiapine, Olanzapine); anticonvulsants (Carbamazepine); antiemetics/travel sickness (scopolamine); and topical ophthalmoplegics (Cyclopentolate, Homatropine) (Kiesel etal.,2018). 3.1.2.5 QT- prolongation. Physicians prescribing opioids should consider obtaining an ECG with assessment of the QT interval prior to starting a prescription with methadone, oxycodone (>100mg/d) and tramadol in patients with cardiovascular diseases or patients taking medications with known effect on the QT interval. In patients with prolonged QT interval, the prescription of these opioids should be considered to be avoided. Good clinical practice statement. Consensus/ strong Consensus (14/15; 10/10). Comment: Available data indicate that some opioids such as methadone are highrisk even at low doses, and have the potential for a dosedependent prolongation of the QT interval and development of ventricular tachycardia (Krantz etal.,2003). Some opioids such as tramadol and oxycodone are intermediate risk medications and may develop long QT interval and ventricular tachycardia in high doses. Some other opioids such as morphine and buprenorphine are lowrisk medications and do not produce QT interval prolongation in at least in routine doses (Behzadi etal.,2018). Therapeutic and supratherapeutic doses of tapentadol do not affect the QT/QTc interval in healthy subjects (Oh etal.,2010). 3.1.3 | Special patient groups 3.1.3.1 People aged ≥65years. Physicians prescribing opioids should consider starting with a low dose, increasing the dose slowly (if needed), and close monitoring of efficacy and tolerability. Good clinical practice statement. Strong Consensus (15/15; 10/10). Comment: Agerelated pharmacodynamic and pharmacokinetic changes lead to a longer duration of action of opioids in old age. For these reasons, it is recommended to start opioid therapy with an approximately 25%– 50% dose reduction compared to younger patients and to increase the dose more slowly (Busse et al., 2017). A systematic review of 23 placebocontrolled RCTs with patient populations with chronic musculoskeletal pain and an average age >60years found low average effects of opioids on pain and disability. Termination rates with opioids were four times higher than with other analgesics (Megale etal.,2018). Maximum starting dose should be 30mg MEQ/d. 3.1.3.2 Frailty and/or multimorbidity. Physicians prescribing opioids should consider starting with a low dose, increasing the dose slowly (if needed), and close monitoring of efficacy and tolerability. Good clinical practice statement. Strong Consensus (16/16; 11/11). Comment: The maximum starting dose should be 30mg MEQ/d. For details see Abdulla etal.(2013). 3.1.3.3 Neurodegenerative diseases (including cognitive impairment). Physicians prescribing opioids should consider starting with a low dose, increasing the dose slowly (if needed), and close monitoring of efficacy and tolerability. Good clinical practice statement. Consensus/strong consensus (15/16; 11/11). Comment: A systematic review of case– control studies on neuropsychological effects of LTOT for CNCP found that opioids reduce attention when compared with treatments not targeted on the CNS. If opioids are used together with antidepressants and/or anticonvulsants, this effect increases (Allegri etal.,2019). There is currently a lack of evidence to support safety evaluations of commonly used analgesics in patients with dementia (Erdal etal.2019). In a placebocontrolled RCT in patients with advanced dementia and depression, transdermal buprenorphine had a significantly higher risk of discontinuation compared with placebo in people with advanced dementia and depression, mainly due to psychiatric and neurological adverse events. Daytime activity dropped significantly during the first week of treatment. Concomitant use of antidepressants further reduced the tolerability of buprenorphine (Erdal etal.,2018). 3.1.3.4 Current severe affective disorder and/or suicidal ideation (F32- 34). Physicians prescribing opioids should consider not starting opioid prescription when there is current severe affective disorder and/or suicidal ideation. Good clinical practice statement. Strong Consensus (16/16; 11/11). Comment: Longterm opioid therapy increases the risk of incident, recurrent and treatmentresistant depression. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 974 | KRČEVSKI ŠKVARČ et al. Depressed patients may tend to overuse opioids because they use them to treat insomnia and stress. Depression also seems to increase the risk of abuse or nonmedical use of prescription opioids among adults and adolescents (Sullivan,2018). Therefore, current severe affective disorder and/or suicidal ideation should be successfully treated by psychiatricpsy- chotherapeutic interventions before initiating opioid therapy. 3.1.3.5 Children and adolescents. Opioids should be considered for use only in exceptional cases and in specialized centres for pain therapy in children and adolescents. Good clinical practice statement. Strong Consensus (15/15; 10/10). Comment: There are no RCTs of opioids for CNCP in children and adolescents available (Cooper et al., 2017). Our statement is based on the potential risks of opioids (e.g., opioid use disorder, endocrinological changes). 3.1.3.6 Pregnancy and medically indicated opioid therapy. Opioid therapy can be considered for the termination in a stepwise fashion if pregnancy occurs during ongoing therapy with opioids. Good clinical practice statement. Consensus (12/14; 8/9). Comment: The database for the use of opioids (and other analgesics) in pregnancy is limited. Only paracetamol is generally allowed in pregnancy in all trimesters. For all opioids, an insufficient experience is reported in www.embry otox. de. For treatment during pregnancy, morphine, tramadol, buprenorphine (50– 300 systematically evaluated pregnancies) are most likely to be recommended, without fundamental reservations against other opioids (fentanyl, oxycodone, hydromorphone). There is little experience with tilidine/naloxone (<50 pregnancies) and no experience with tapentadol (Australian Government, 2020). In breastfeeding women, the ultrarapid conversion of codeine to morphine can result in high and unsafe levels of morphine in blood and breast milk. The U.S. Food and Drug Administration has strengthened the label warning to state that breastfeeding is not recommended while using medicines containing codeine or tramadol because of the potential for serious adverse effects in the infant due to opioid overdose (Food & Drug Admininstration,2019). In the case of discontinuation, withdrawal symptoms should be avoided as this is associated with an increased risk of premature labour and miscarriage or premature birth. Care in opioid weaning should be exercised as opioid withdrawal can precipitate premature delivery (Reddy et al., 2017). In the case of an indicated analgesia that cannot be achieved otherwise, it may be necessary to continue therapy with opioid analgesics during pregnancy. The delivery should then take place in a stage I/II perinatal centre, as neonatal abstinence syndrome (NAS) is very likely in the newborn (Reddy et al., 2017). 3.1.3.7 Pregnancy and abuse/dependence of opioids prescribed for medical reasons. Methadone/polamidon or buprenorphine as medicationassisted therapy should be considered for use in close cooperation of obstetricians/ gynecologists, pain physicians and mental health care specialists. Good clinical practice statement. Strong Consensus (13/13; 8/8). Comment: The World Health Organization (2014) support methadone and buprenorphine as medication treatment options for pregnant women with opioid use disorder. However, recent studies indicate that buprenorphine has advantages over methadone (Rausgaard et al., 2020). 3.1.3.8 Breastfeeding and abuse/dependence of opioids prescribed for medical reasons. Methadone/polamidon or buprenorphine as medicationassisted therapy should be considered to use in close cooperation of obstetricians/gynecologists, pain physicians and mental health care specialists to enable breastfeeding as an integral component of theearly management of neonatal abstinence syndrome. Good clinical practice statement. Strong Consensus (13/13; 8/8). Comment: Neonatal abstinence syndrome is a neurological condition resulting from prenatal exposure to opioids. The sudden cessation of opioids in neonates can lead to withdrawal symptoms affecting the neurological, respiratory and gastrointestinal systems. With rare exception, breastfeeding is the optimal way to feed infants and has special benefits for women and infants with perinatal opioid exposure. Infants breastfed and/or fed their mother's own breastmilk experience less severe opioid withdrawal symptoms, have shorter hospital stays, and are less likely to be treated with medication for withdrawal (Wu & Carre,2018). 3.1.3.9 Current substance abuse and dependence (alcohol, cannabinoids, opioids, cocaine, tranquilizer, others). An indicated therapy with opioids should only be considered to be conducted in close collaboration with an addiction mental health care specialist. Good clinical practice statement. Strong Consensus (17/17; 12/12). 3.1.3.10 Homeless and Vulnerably Housed Persons. Physicians should consider providing homeless persons with access to pain management programs including supervised access to opioids – if indicated. Good Clinical Practice Statement. Strong Consensus (17/17; 12/12). Comment: A coordinated, interagency and multifaceted approach is required to address the underlying structural, cultural and societal factors that contribute to homelessness and its stigmatization. In the interim, we need to develop more tailored and accessible services to ensure that the homeless in our societies receive better health care, including pain management. This will require the provision of supervised access to opioid analgesics for carefully selected and supervised persons in a way that minimizes potential harm. In particular, robust strategies to minimize the risk of medication misuse and diversion must be in place (Magwood etal.,2020). 3.1.3.11 Prisoners: Physicians should consider providing persons in custodial settings with access to pain management programs including supervised access to opioids – if indicated. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 975 KRČEVSKI ŠKVARČ et al. Good Clinical Practice Statement. Strong Consensus (17/17; 12/12). Comment: Prisoner feedback identifies four areas of concern: 1. Delays in accessing treatment. 2. Prisoners reported that healthcare staff are not perceived as caring and do not always appear to take prisoners' reports of pain seriously. 3. Inconsistencies in approaches adopted by different clinicians, particularly when prisoners are moved from one custodial setting to another. 4. A perceived reluctance to prescribe opioids when simple nonopioid analgesics prove ineffective. In prisons, there are additional risks associated with the use of controlled medications including a high prevalence of mental health problems, medication dependence and the potential for diversion and misuse. In circumstances where an appropriate physician evaluation has occurred and the physician is satisfied that a trial of opioid medication is indicated, such therapy may be warranted and appropriate. As in all circumstances where opioids are prescribed, each patient must be kept under close clinical surveillance and every precaution must be taken to ensure the safekeeping and security of prescribed medications. In prisons, the issue of opioid diversion or abuse is particularly problematic and may result in harm to the individual prisoner or other inmates. In July 2014, the Prison Healthcare Board and the National Offender Management Service in the UK developed a national prison pain management formulary. When implemented across a national prison service, such a formulary supported (Bradshaw etal.,2017): • Greater consistency in evidencebased prescribing • Greater consistency when patients transfer from one custodial setting to another • Reassurance to the prescribing clinician that the formulary incorporates evidencebased guidance with due regard to the known risks associated with the clinical setting • Greater transparency and standardization on the use of prescribed medicines as part of pain care pathways in custodial settings A prison formulary provides a rational, evidencebased approach to the use of analgesic medications for people in prisons (Health & Justice Clinical Reference Group NHS England,2017). 3.1.4 | Comorbidities 3.1.4.1 Renal impairment: In case of advanced renal insufficiency (CKD 4: eGFR<30ml/min), buprenorphine, fentanyl or hydromorphone should be considered as preferred. Other opioids can be used carefully, but dose education and careful observation are required. Good clinical practice statement. Strong Consensus (14/14; 9/9). Comment: In the few available studies, no clear benefits of certain opioids in cases of impaired renal function can be deduced. Recommendations for the use of specific opioids are based mainly on theoretical pharmacokinetic considerations (Mallappallil etal.,2017). eGFR 30– 89ml/min: All opioids can be used with consideration of reduced dose or frequency. Dose titration should start with lower doses than usual, but should be based on clinical efficacy. Every opioid should be titrated individually, dosing of opioids in renal impairment should be guided by the clinical effect and side effects, not only by biochemistry. Dose reduction or extended dose interval is recommended for transdermal fentanyl, hydromorphone, morphine, oxycodone, tilidine and tramadol. In the case of tapentadol, a dose adjustment is not necessary in the case of slightly or moderately impaired renal function. For severely impaired renal function, use is not recommended due to the lack of data. No dose reduction necessary: Buprenorphine transdermal. eGFR<30ml/min: Buprenorphine, fentanyl or hydromorphone should be preferred. Haemodialysis: Buprenorphine, fentanyl or hydromorphone should be preferred. Hydromorphone morphine and tramadol are dialysable. Buprenorphine, fentanyl and methadone are not dialysable (King etal.,2011). Practice tool: Online tool for dose adjustment in renal failure of the Pharmacology Department of the University of Heidelberg: http://dosing.de/ 3.1.4.2 Liver cirrhosis: Opioids can be considered when carefully used, but dose reduction and careful observation is needed. Good clinical practice statement. Strong Consensus (14/14; 9/9). Comment: In the few available studies, no clear benefits of certain opioids in cases of impaired liver function can be deduced. Recommendations for the use of specific opioids are therefore based mainly on theoretical pharmacokinetic considerations. Every opioid should be titrated individually, dosing of opioids in hepatic impairment should be guided by the clinical effect and side effects, not only by biochemistry. Opioids can be given in patients with liver cirrhosis under close surveillance with cautiously increasing dosage (risk of triggering hepatic encephalopathy, major adverse effects or opioid overdose). Particular attention should be paid to the prevention of constipation in these patients. Note for the dose recommendations for opioids in liver cirrhosis below that due to shunts, changes in first pass metabolism, albumin binding etc. that cannot be easily quantified, dosages are highly individual and adverse effects unpredictable Donbe. Dose recommendations for opioids in liver cirrhosis (modified according to Weersink etal.,2018). 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 976 | KRČEVSKI ŠKVARČ et al. Medication Child A Child B Child C Buprenorphine No dose adjustment needed Start with half of usual dose Start with half of usual dose Fentanyl Start with half of usual dose Start with half of usual dose Start with half of usual dose Hydromorphone Start with a quarter of usual dose Start with a quarter of usual dose Start with a quarter of usual dose Morphine Start with half of usual dose Start with half of usual dose Start with a quarter of usual dose Oxycodone Start with a quarter of usual dose Start with a quarter of usual dose Start with a quarter of usual dose; double interval between dosages Tapentadol No dose adjustment needed Start with 50mg, maximum 150mg/d Not recommended Tramadol Start with 50mg, maximum 200mg/d Start with 25mg, maximum 100mg/d Start with 25mg, maximum 100mg/d 3.1.4.3 Short bowel syndrome: Liquids, capsules and uncoated tablets or transdermal applications can be considered as preferred over oral modifiedrelease formulations (slowrelease, controlledrelease or sustainedrelease) opioids. Good clinical practice statement. Strong Consensus (13/13; 8/8). Comment: Patients with short bowel syndrome (SBS) may be at risk for impaired absorption of oral medications. Most medications are absorbed in the stomach and proximal small bowel, and thus their effect is preserved. Entericcoated medications and timed/delayedrelease medications, in contrast, may not be absorbed properly and should generally be avoided. When feasible, alternative methods for medication delivery (e.g., liquid, transdermal, suppositories) should be used and medication levels should be monitored (UptoDate,2020). Patients with less than 2 meters of the gut are at risk of short bowel syndrome, which can result in compromised absorption of opioids. On the other hand, opioids are also prescribed as antidiarrhoeal agents by gastroenterologists in short bowel syndrome to treat hypermobility. Preference should be given to dispersible formulations if they are available. Formulations such as liquids, capsules and uncoated tablets are likely to be better absorbed. It may be necessary to avoid oral modifiedrelease formulations (slowrelease, controlledrelease or sustainedrelease) opioids. If a solid dose form of an opioid is to be altered, there is a potential for a shift in side effects and efficacy. A common strategy to improve medication bioavailability in short bowel syndrome is to increase the prescribed dose – even beyond that ‘recommended’. The effect can be monitored by evaluating the balance between analgesia and side effects. Careful monitoring for systemic side effects such as drowsiness, sedation and respiratory depression, especially during the initiation and dose titration phase, are crucial to minimize the risks associated with oral opioids in short bowel syndrome. Patients with a colostomy are unlikely to suffer significant problems with opioid absorption as opioids are absorbed in the stomach and proximal small intestine. Normal doses and formulations can be used for most patients. In patients with small intestinal stomas (jejunostomy or ileostomy), the ability to use medications normally is largely dependent on the residual length of the small intestine and more dispersible formulations are likely to be better absorbed. Methadone has some unique pharmacokinetic properties which makes it a valuable option in short bowel syndrome. It is a very lipophilic medication and oral methadone has a bioavailability of nearly 80% of the administered dose compared to 26% for morphine. It is absorbed rapidly from the stomach, and most absorption occurs before transiting beyond the stomach. 3.1.5 | Management of complications 3.1.5.1 Constipation: Treatment with laxatives should be considered prophylactically in most patients. Good clinical practice statement. Consensus (14/15; 9/10) Comment: About 60%– 80% of patients in opioid therapy suffer from side effects from the gut. Constipation is the predominant complaint, but nausea (partly a central side effect), vomiting, abdominal pain, and distension etc. are also frequently seen (Farmer etal.,2019). A decision regarding the use of prophylactic therapy for constipation and other opioidrelated side effects in the gut is necessary and must be made in each individual case depending on the symptoms. It is a common mistake to define constipation as number of bowel movements, but straining, gas production, hard consistency of stools and abdominal discomfort are more frequent symptoms that need to be taken into consideration. A decision about a prophylactic laxative therapy, if necessary, must be made in each case and depending on the defecation pattern of the patient. In patients with a preexisting constipation (tendency), the prophylactic administration of laxatives is recommended. In many patients, the administration of laxatives may be necessary during the entire duration of therapy with opioidcontaining analgesics. According to the clinical experience of the TF, the constipationpromoting effect of opioids may vary between patients. The preference of a specific medication (including peripherally acting opioid antagonists for prophylaxis and therapy of opioidinduced constipation) is not possible due to variation in practice between countries. Suggestions for 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 977 KRČEVSKI ŠKVARČ et al. a stepwise medication (including peripherally acting opioid antagonists) approach can be found in the literature (e.g., Farmer etal.,2019). 3.1.5.2 Nausea and vomiting: An antiemetic treatment can be considered in some patients at the beginning of the therapy. After about 2– 4weeks, discontinuation of antiemetic therapy should be considered. Good clinical practice statement. Strong Consensus (15/15; 10/10). Comment: According to the clinical experience of the TF, the emetic effect of opioids may vary between patients. Opioidinduced nausea and vomiting are experienced by up to 40% of pain patients with no history of emesis. However, because this is an inconsistent consequence of opioid therapy, prophylactic antiemetics are generally not prescribed. In most patients, tolerance to the emetic effect of opioids develops after 2– 4weeks, routine administration of antiemetics is not necessary. There are no controlled studies on the use of antiemetics for the treatment of opioidinduced nausea in CNCP. The preference of a specific medication for prophylaxis and therapy of opioidinduced constipation is not possible due to variation in practice between countries. Antihistamines, neuroleptics, prokinetics and setrons (5- HT3 receptor antagonists) may be used. 3.1.5.3 Psychiatric side effects: If somnolence, delirium, hallucinations, nightmares, persistent anxiety/depression suicidal ideation occur, dosages should be considered for reduction as much as possible or therapy should be considered to be switched to another opioid. Good clinical practice statement. Strong Consensus (15/15; 10/10). Comment: For details see Sivanesan et al., 2016. Psychiatric consultation should be considered. 3.1.5.4 Myoclonic movements: If myoclonic movements occur, dosages should be considered for reduction as much as possible or therapy should be considered to be switched to another opioid. Good clinical practice statement. Strong Consensus (16/16;11/11). Comment: Myocloni mainly occur by a glucuronide metabolite of morphine and hydromorphone accumulation in renal impairment (Mercadante,1998). 3.1.5.5 Increase of pain severity. In case of an increase of pain severity, a clinical assessment should be considered to differentiate between progression of the disease, tolerance and opioidinduced hyperalgesia. Good clinical practice statement. Strong Consensus (15/15; 10/10). Comment: It is important to identify different reasons for increase of pain intensity prior to a change in management plan: Progression of the disease: In some CNCP syndromes, the clinical picture can deteriorate, which in turn can lead to an increase in nociception. For example, in the case of osteoarthritis, the movementdependent pain can be increased with damage of the joint cartilage. Tolerance: Tolerance to opioid analgesia may develop after ongoing exposure to the drug. The same dose of drug administered over time produces less analgesic effect. The rate of onset and extent of tolerance development is variable depending on the individual drug and patient characteristics (Colvin etal.,2019). Opioidinduced hyperalgesia (OIH): There are no internationally accepted and/or validated criteria to diagnose. OIH can be considered present when symptoms worsen even with an increase in opioid dose (and worsening in disease/ tolerance have been excluded) and when these symptoms and signs are present: (i) increased nociception over time (ii) tendency to spread to other areas (iii) hyperalgesia to external stimuli (Colvin etal.2019). Suggested Clinical Criteria for Diagnosing OIH (Eisenberg etal.,2015): • Increased pain intensity during ongoing opioid treatment. • No evidence for underlying disease progression. • No evidence for either clinical or pharmacological opioid withdrawal (i.e., symptoms and signs of opioid withdrawal; increased pain as a result of the end of previous opioid dose effect). • No evidence for opioid tolerance: to be tested clinically by decreased pain in response to an adequate opioid rescue dose. • Decrease in pain intensity in response to a reduction in opioid dose (gradual dose reduction might be required to avoid abstinence syndrome). • No evidence for addictive behaviour. OIH can be differentiated from worsening in disease and tolerance by reducing dose and monitoring response (Colvin etal.,2019). 3.1.5.6 Opioid induced hyperalgesia. Opioids should be considered for reduction as much as possible. Good clinical practice statement. Strong Consensus (15/15; 10/10) Comment: For details see Bannister (2015). 3.1.5.7 Tolerance. In case of tolerance development, a dose increase (bearing in mind guidance on opioid dose limits), opioid switch or opioid withdrawal should be considered. Good clinical practice statement. Strong Consensus (15/15; 10/10). Comment: In the context of LTOT, there may be a reduction in analgesic effectiveness (tolerance). As a rule, no more than two opioid changes should be carried out with tolerance development. Continued tolerance development with a repeated need for dose adjustment even after opioid changes is not useful for obtaining a clinically relevant effect (responder). Instead of a further opioid rotation, a stepwise opioid reduction or opioid withdrawal should be performed. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. 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Eur J Pain. 2021;25:969– 985. https://doi.org/10.1002/ejp.1744 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1744 by Readcube (Labtiva Inc.), Wiley Online Library on [14/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License