European* clinical practice recommendations on opioids for chronic noncancer pain – Part 1: Role of opioids in the management of chronic noncancer pain

Eur J Pain. 2021;25:949–968. | 949 wileyonlinelibrary.com/journal/ejp DOI: 10.1002/ejp.1736 POSITION PAPER European* clinical practice recommendations on opioids for chronic noncancer pain – Part 1: Role of opioids in the management of chronic noncancer pain WinfriedHäuser1,2 | BartMorlion3 | Kevin E.Vowles4 | KirstyBannister5 | EricBuchser6 | RobertoCasale7 | Jean- FrançoisChenot8 | GillianChumbley9 | Asbjørn MohrDrewes10 | GeertDom11 | LiisaJutila12 | TonyO‘Brien13 | EstherPogatzki- Zahn14 | MartinRakusa15 | CarmenSuarez– Serrano16 | ThomasTölle17 | NevenkaKrčevski Škvarč18 1Department Internal Medicine 1, Klinikum Saarbrücken, Saarbrücken, Germany 2Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München, Munich, Germany 3Center for Algology & Pain Management, University Hospitals Leuven, Leuven, Belgium 4School of Psychology, Queen's University Belfast, Belfast, UK 5Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK 6Pain Management and Neuromodulation Centre EHC Hospital, Morges, Switzerland 7Neurorehabilitation Unit, Department of Rehabilitation, HABILITA, Bergamo, Italy 8Department of General Practice, Institute for Community Medicine, University Medicine Greifswald, Germany 9Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK 10Mech- Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Denmark 11Collaborative Antwerp Psychiatric Research Institute (CAPRI), Antwerp University, Antwerpen, Belgium 12Pain Alliance Europe, Finland 13College of Medicine & Health, University College Cork, Cork, Republic of Ireland 14Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster UKM, Munster, Germany 15Department of Neurology, University Medical Centre, Maribor, Slovenia 16Department of Physiotherapy, University of Sevilla, Sevilla, Spain 17Department of Neurology, Techhnische Universität München, München, Germany 18Department of Anesthesiology, Intensive Care and Pain Treatment, Faculty of Medicine of University Maribor, Maribor, Slovenia 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. 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 complex. In the absence of pan- European guidance on this issue, a position paper was commissioned by the European Pain Federation (EFIC). 950 | HÄUSER Et al. 1 | INTRODUCTION In 2017, the European Pain Federation (EFIC) published a position paper on appropriate opioid use in chronic pain management (O'Brien etal.,2017). The position paper did not differentiate between management of chronic cancer and noncancer pain (CNCP). The importance of opioids in the management of cancer pain and in palliative care is internationally accepted although the amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low (Wiffen etal.,2017). The opioid crisis in North America (DeWeerdt,2019) led to an update of the Canadian guideline on opioids for CNCP (Busse etal.,2017; Furlan etal.,2010) and to a guideline from the United States (US) Centers for Disease Control (CDC) (Dowell etal.,2016), which focused on harm reduction in relation to opioid prescribing for CNCP. Furthermore, several US authors have discussed their concerns that the opioid crisis reflects shortcomings of the North American health care systems (Dasgupta etal.,2018; Sullivan & Howe,2013). Although European countries are far from the opioid crisis in North America (Chenaf etal.,2019; Häuser et al., submitted; Kalkman etal.,2019; National Records of Scotland,2018; Rosner etal.,2019), there are increasing concerns about the safety of longterm opioid therapy (LTOT) for patients with CNCP (Ballantyne,2016). Therefore, EFIC commissioned a Task Force (TF) to update their position paper on appropriate opioid use specifically for CNCP and to separate it from cancer pain. In 2019, standards for the management of cancerrelated pain across Europe from the EFIC Task Force on Cancer Pain were published (Bennett etal.,2019). By including other 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, casecontrol 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 key clinical practice recommendations suggest: (a) first optimizing established nonpharmacological treatments and nonopioid analgesics and (b) considering opioid treatment if established nonpharmacological treatments or nonopioid analgesics are not effective and/or not tolerated and/or contraindicated. Evidence- and clinical consensusbased potential indications and contraindications for opioid treatment are presented. Eighteen GCP recommendations give guidance regarding clinical evaluation, as well as opioid treatment assessment, monitoring, continuation and discontinuation. Conclusions: Opioids remain a treatment option for some selected patients with CNCP under careful surveillance. Significance: In chronic pain, opioids are neither a universal cure nor a universally dangerous weapon. They should only be used for some selected chronic noncancer pain syndromes if established nonpharmacological and pharmacological treatment options have failed in supervised pain patients as part of a comprehensive, multimodal, multidisciplinary approach to treatment. In this context alone, opioid therapy can be a useful tool in achieving and maintaining an optimal level of pain control in some patients. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 | 951 HÄUSER Et al. European health professional societies, the paper was renamed as European Clinical Practice Recommendations (ECPRs). This paper concerns opioids for CNCP and aims to promote the responsible use of opioids for CNCP by: • discussing the role of opioids in the management of CNCP. • identifying potential indications, contraindications and advice for discontinuation of opioids. • providing recommendations for Good Clinical Practice (GCP; e.g. dosing; selection of opioids; monitoring side effects). • discussing the role of opioids in specific patient populations. • giving recommendations for the management of specific adverse events of opioids. 1.1 | Scope The purpose of the ECPRs is to support appropriate decision making and, if warranted, appropriate prescribing of opioids for patients of any age with chronic (persistent or recurrent >3months) noncancer pain. The target audience includes: • all health care professionals (physicians, psychologists, nurses, occupational therapists, physiotherapist, pharmacists) supporting patients with CNCP. • those who take opioids (patients) and their significant others. • those who create opioid prescribing policy. These clinical practice recommendations discuss all oral and transdermal opioids which can be prescribed for chronic pain management in Europe (buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, polamidone, tilidine), including opioids with a twoway mode of action (tapentadol and tramadol). Combination products of opioids with other analgesics, such as paracetamol, are not covered. The ECPR is focused on LTOT for CNCP. Therefore, it does not address the management of acute or subacute pain (<4 weeks) treatment (including acute pain episodes of chronic diseases such as sickle cell disease), end of life care, or the use of opioids for nonpainful conditions such as opioid use disorder. Definitions of LTOT vary widely. Most studies define longterm as ≥12weeks of opioid use (Karmali etal.,2020). Based on study duration of RCTs, we have made a classification for duration of opioid therapy for evidencebased recommendations for potential indication of opioids: shortterm (4– 12weeks), intermediateterm (13– 26weeks), longterm (>26weeks). 1.2 | Disclaimer The ECPRs are not intended to contradict diseasespecific evidencebased guidelines. They are expert consensus statements rather than a guideline and incorporate the expertise of the TF membership. The TF members acknowledge the conclusions of robust evidencebased guidelines but the clinical practice recommendations recognize that individual responses to therapy may differ from average responses described in evidencebased guidelines. The ECPRs represent a consensus statement of healthcare professionals who work with people with pain provides an experienced perspective, acknowledging the evidence, to support clinical decision making. The ECPRs do not represent a regulation of action or omission, which has been agreed by a legally legitimate institution, fixed in writing and published. It is not binding for the legal area of an institution and will not result in defined sanctions, if not followed. Recommendations only become clinically effective if the strength of recommendation is considered and integrated in individual patient care, including shareddecision making with patients. The decision as to whether a certain strength of recommendation should be followed must be made by physicians, considering the circumstances of individual patients and the available resources. 2 | METHODS 2.1 | Task force membership The TF included 17 members (6 female) from nine European countries (North, Central, East and South Europe and UK). Nine delegates were nominated by EFIC's board. The board selected delegates who advocate and who are critical with the use of opioids for CNCP. Seven delegates representing members of the European Pain Forum (https://europ eanpa infed erati on.eu/advoc acy/curre ntproje cts/europ eanpain- forum/) volunteered to contribute. These delegates were selected because of their clinical and/or scientific expertise. One delegate of the Pain Alliance Europe (PAE) participated as a patient representative. The TF included most health care professions (medicine, nursing, physiotherapy, psychology) caring for patients with chronic pain. The medical specialties of the physicians were anesthesiology, gastroenterology, general practice/family medicine, general internal medicine, neurology, pain medicine, palliative care, physical and rehabilitation medicine, psychiatry, psychosomatic medicine (see Table1). 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 952 | HÄUSER Et al. TABLE 1 Composition of the task force TF member Gender Specialty Country Nominated by Assessment of financial COIs related to the topic of the paper Bannister, Kirsty Female Pharmacology Great Britain EFIC None Buchser, Eric Male Anesthesiology Switzerland European Society of Regional Anesthesia None Casale, Roberto Male Physical and Rehabilitation Medicine Italy European Society of Physical and Rehabilitation Medicine None Chenot, Jean- François Male General Practice/Family Medicine Germany EFIC None Chumbley, Gillian Female Nursing Great Britain EFIC None Doom, Geert Male Psychiatry Belgium European Psychiatric Association AND European Federation of Addiction Societies None Drewes, Asbjorn Male Internal Medicine/ Gastroenterology Denmark EFIC moderate Häuser, Winfried Male Internal Medicine, Psychosomatic Medicine Germany EFIC None Jutila, Liisa Female Patient representative Finland Pain Alliance Europe None Krcevski- Škvarč, Nevenka Female Palliative care medicine Slovenia EFIC None Morlion, Bart Male Anesthesiology Belgium EFIC Moderate O'Brien, Tony Male Palliative care medicine Ireland EFIC Moderate Pogatzki- Zahn, Esther Female Anesthesiology Germany European Society of Anaesthesiology Moderate Rakusa, Martin Male Neurology Slovenia European Academy of Neurology None Suarez - Serrano, Carmen Female Physiotherapy Spain European Region of the World Confederation of Physical Therapy None Tölle, Thomas Male Neurology Germany EFIC Moderate Vowles, Kevin Male Psychology Great Britain European Federation of Psychologists Associations None Abbreviation: EFIC, European Pain Federation. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 | 953 HÄUSER Et al. 2.2 | Managing conflicts of interest All TF members declared any potential conflicts of interest (COIs) before the start of the update using the Form for Disclosure of Potential Conflicts of Interest from the International Committee of Medical Journal Editors (http:// www.icmje.org/confl icts- of- inter est/). Potential COIs were independently evaluated by two representatives of EFIC (Sam Kynman, Executive Director and Prof. Hans Georg Kress, Chair of Ethics Committee), who did not participate in the development of this paper. Discrepancies were resolved by consensus. The degree of financial COIs with pharmaceutical companies producing opioids was classified into none, slight, moderate, high, defined as follows: • None: No interaction. • Slight: Only honoraria for lectures. • Moderate: Advisory board; study support. • High: Patent; employee of a pharmaceutical company. Twelve members of the TF had no COIs, including the three TF chairs (Häuser, Krcevski- Škvarč, & Vowles). Five members had moderate financial COIs (Drewes, Morlion, O'Brien, Pogatzky- Zahn, Tölle). Secretarial support for the drafting of this position paper came from EFIC. The funding of EFIC is detailed in its most recent annual reports which can be found on the EFIC website https://europ eanpa infed erati on.eu/howwe- work/annua lrepor t/. The funding of PAE is detailed in https://paeeu. eu/activ ities/. 2.3 | Key questions The key questions to be addressed were defined by a Delphi round of theTF. Four recent national (Canada, France, Germany, USA; Busse et al., 2017; Dowell et al., 2016; Moisset & Martinez,2016; Häuser etal.,2020) guidelines on opioids for CNCP were provided to the members of the TF by the evidence synthesis team to inform the process. The key questions are outlined in Supplementary Material 1. 2.4 | Search strategy For the review of potential opioid indications and contraindications, we focused on systematic reviews (with or without metaanalysis) of randomized controlled trials (RCTs) of opioids for CNCP with at least 4weeks doubleblind duration and open label extensions studies of these trials with at least 6months duration and evidencebased guidelines concerned with the management of CNCP. The evidence synthesis team (Häuser, Welsch) conducted the searches. PubMed was searched on 11 February 2020 (from 2015) with the search terms [‘opioid’ AND ‘chronic pain’ AND ‘systematic review’]. PROSPERO was searched 8 March 2020 with the search terms [‘opioids’ and ‘chronic noncancer pain’]. For the section on special situations, we conducted a selective search of literature in PubMed in April 2020 with the search term [‘opioids’] and the respective term of the GCP statement. The literature for the ECPRs was selected by the members of the evidence synthesis team. The reference lists of the systematic reviews and guidelines selected were also considered for the recommendations and clinical practice statements of the position paper. Discrepancies were resolved by consensus. 2.5 | Summary of evidence The patient representative was involved in defining the key questions, providing recommendations and good clinical practice statements, and the evaluation of the patient version of the clinical practice recommendations. The evidence synthesis team created evidence summaries based on the selected systematic reviews. The selection of outcomes of interest was based on the recommendations of the ACTINPAIN writing group of the International Association for the Study of Pain's (IASP) Special Interest Group on Systematic Reviews in Pain Relief (Moore et al., 2010) and the guideline on the clinical development of medicinal products intended for the treatment of pain of the European Medicines Agency (2017). These outcomes included: 1. Pain relief from baseline of 30% or greater 2. Patient global impression to be much or very much improved 3. Disability 4. Drop out rates to adverse events 5. Serious adverse events 6. Death 7. Nonmedical use/dependence We used the systematic review with the most recent search of literature or the most studies included in the analyses. If reported, the GRADE system was used for the evidence summaries to provide a description of benefits and harms, along with a rating of the certainty of the evidence on an outcomeby- outcome basis (Langendam etal.,2013). If no GRADE rating was available, we used the UpToDate® rating of the quality of evidence (UptoDate,2020a, 2020b). 2.5.1 | Patient preferences Pain Alliance Europe (PAE) conducted a survey with some member countries (Spain, Romania, Belgium, UK, Sweden 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 954 | HÄUSER Et al. and Finland) on the importance of potential positive and negative effects taking a new medication for the chronic pain management from 22 May to 2 June 2020. The potential positive and negative effects of medications (related to opioids) were selected by three TF members (two physicians, one patient representative). In total, 131 PAE members participated (78% females). The details of the patient survey are outlined in Supplementary Material 2. Important or very important positive and negative effects were rated as follows: • Positive effects a. Pain relief of 50% or more: 74% of the respondents. b. Pain relief of 30% or more: 92% of the respondents. c. Improvement of daily functioning: 91%. d. Improvement of sleep: 82%. • Negative effects a. Somnolence: 66%. b. "Addiction": 58%. c. Sexual problems: 45%. In addition, a search in PubMed [‘patient preferences’ AND ‘opioids’ AND ‘CNCP’) in 6 February 2020 produced 6 hits. We found one systematic review, which ranked pain relief, nausea and vomiting as highly significant negative outcomes across studies. When considered in the studies, the adverse effect of personality changes was rated as equally important. Constipation was assessed in most studies and was an important outcome, but secondary to pain relief, nausea and vomiting. The only two studies that evaluated addiction, found it less important to patients than pain relief (Goshua etal.,2018). 2.6 | Development of recommendations and GCP statements This paper includes two categories of guidance: Evidencebased recommendations (supported by evidence from systematic reviews of RCTs or of observational studies) and GCP statements (supported by either indirect evidence or by single RCTs, caseseries, casecontrol studies or clinical experience). We applied the GRADE system to move from evidence to recommendations if systematic reviews with GRADE ratings were available (Andrews etal.,2013). We used UptoDate rating of quality of evidence, if systematic reviews with GRADE ratings were not available (see Table2). All members of the TF completed the Uptodate® Grading tutorial (https://www.uptod ate.com/home/gradi ngtutor ial#). Evidencebased recommendations could be made ‘for’ or ‘against’. The strength of a recommendation could be ‘strong’ or ‘weak’ (see Table3). For a strong recommendation, we noted, ‘We recommend’. For a weak recommendation, we noted, ‘We suggest’. Similarly, GCP statements could be made ‘for’ or ‘against’ with the terms ‘should be considered’ (valid for nearly all patients) and ‘can be considered’ (valid for the majority of patients) (see Table3). The TF is aware that there are controversies or disparities in interpretation of the evidence (e.g. of the RCTs for CLBP). Quality rating Rationale Strong Consistent evidence from well performed randomized, controlled trials or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk. Moderate Evidence from randomized, controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence of some other form. Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate. Low Evidence from observational studies, unsystematic clinical experience, or from randomized, controlled trials with serious flaws. Any estimate of effect is uncertain. Note: The general categories that lower the quality of evidence from RCTs are: Methodologic problems likely to cause bias: • Inconsistent results • Indirectness of evidence • Few observed events The factors that may raise the quality of evidence from observational studies are: • Large magnitude of effect • All plausible biases would reduce a demonstrated effect • Doseresponse gradient TABLE 2 Rating of the quality of supporting evidence according to UptoDate® 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 | 955 HÄUSER Et al. Therefore, our evidencebased recommendations are based on clinical experience, too. 2.7 | Consensusfinding procedure The evidencebased recommendations and GCP statements were initially prepared by the three chairs of the TF (Häuser, Krcevski- Skvarc, & Vowles). These were then discussed, modified and finalized by the TF in seven Delphi rounds. The individual members of the TF then voted online from 1 to 12 June 2020. The group held a final webbased consensus conference on 13 June 2020. All TF members participated in the online voting and all but one in the webbased consensusconference. In this conference, all statements and recommendations which did not reach a consensus of >90% in the online vote were discussed and modified if necessary with the aim to increase the strength of consensus. For both voting procedures TF members had three options: Agree, disagree or abstention (due to lack of expertise). Abstention votes were not included in calculations regarding the strength of consensus. Strength of consensus was classified as follows: strong consensus: >95% agreement; consensus: 75%– 95% agreement; majority: 50%– 75% agreement; no consensus: ≤50% agreement. The strength of consensus was assessed in two ways: With and without the votes of the members with moderate COIs. In the document, the strength of consensus for every recommendation and clinical practice statement is reported as follows in brackets: (votes of all TF members; votes of all TF members without COIs). 2.8 | External reviews The draft ECPR document was sent to five individuals with expertise in opioids for chronic pain, each of whom provided an open review. These individuals included Jane Ballantyne (USA), Andrea Furlan (Canada), Cathy Stannard (UK), Rainer Sabatowski (Germany) and Mark Sullivan (USA). These experts were asked to identify any omissions of important topics, comment regarding evidencebased recommendations or GCPs, provide alternative suggestions if necessary, and comment on methods where important. The heads of the TF drafted replies to the reviewers and suggested changes to evidencebased recommendations, GCP statements and comments in consensus. All suggestions for modifications of this paper were discussed by the TF. Based on the comments of the reviewers, five GCP statements (two on the role of opioids; one on shortversus long acting opioids; one on intake scheme; one on opioidinduced hyperalgesia) were changed with regards to content. One new GCP statement on opioid tapering was added. A Delphi round of the TF to assess the strength of consensus of these five modified GCP statements was conducted. The wording of the strength of recommendation for GCP statements was changed. The wording, but not the content, of eleven GCP statements was changed. Twentyseven comments were also expanded. In the sections ‘background, scope, disclaimer’ six amendments were made. Twelve public comments (11 from health care professionals, one from a pharmaceutical company producing an opioid) were received. All public commentators declared their financial conflicts of interest (available on request): All comments were reviewed and answered by the TF chairs based on consensus. The answers were discussed by the TF members. Seventeen comments were modified (wording, supplements) based on the comments of the health professionals. Based on the comment of the pharmaceutical company, one supplement was made in the section scope and ten comments were modified (wording, supplements). We followed one of six suggestions of the company, to mention their product in the comment. The changes in the ECPRs based on the comments of the reviewers and the public commentators can be provided on request. TABLE 3 How to use and understand the recommendations and good clinical practice statement of the position paper This position paper provides prescribers and patients with a basis for decisions about using opioids to manage chronic noncancer pain. Prescribers, patients and other stakeholders – particularly regulatory agencies or the courts – should not view the recommendations and good clinical practice statements in this guideline as absolute. No guideline can account for the unique features of patients and their clinical circumstances; this guideline is not meant to replace clinical judgment. A strong recommendation means that benefits clearly outweigh risks and burdens or vice versa. It indicates that all or almost all fully informed patients would choose the recommended course of action, and indicate to clinicians that the recommendation is appropriate for almost all patients. A weak recommendation means that benefits, risks, and burdens are closely balanced or uncertain. It indicates that the majority of informed patients would choose the suggested course of action, but an appreciable minority would not. With weak recommendations, clinicians should recognize that different choices will be appropriate for individual patients, and they should help patients arrive at a decision consistent with their values and preferences. The term ‘Should be considered’ in a good clinical practice statement means, that the good clinical practice statement is appropriate for almost all patients. The term ‘Can be considered’ in a good clinical practice statement means, that the good clinical practice statement is appropriate for the majority of patients. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 956 | HÄUSER Et al. 2.9 | Final approval This ECPRs were approved by the board of EFIC and the boards of nine participating member societies of the Pain Forumn and the European Pain Alliance. 2.10 | Publication and dissemination The ECPRs were submitted to the European Journal of Pain in two parts. Part one covers the role of opioids in the management of CNCP, potential indications and contraindications, and GCP of opioid use. Part two covers special situations, including nonmedical use and dependence (Krcevski- Škvarc et al., 2021). A short version for health care professionals will be designed by the TF and be available on the webpage of EFIC. A version for lay persons of the position paper will be developed with PAE. 3 | RESULTS 3.1 | Good clinical practice statements and recommendations 3.1.1 | Part 1: Role of opioids in the management of chronic noncancer pain 1. Optimization of nonopioid treatment. Before considering opioid treatment, we first suggest optimizing nonpharmacological treatments (e.g. exercise, physiotherapy, psychological therapies) and considering nonopioid analgesics. Weak recommendation, strong consensus (16/16; 11/11). Comment: Optimization of nonpharmacological therapies should include interdisciplinary multimodal pain therapy (Kaiser et al., 2017) – if available – and – in selected patients – invasive procedures such as neuromodulation. 2. When to consider opioids. We suggest considering a trial of opioids if established nonpharmacological treatments and established nonopioid analgesics are: • Not effective and/or • Not tolerated and/or • Contraindicated • Not available **Established=Guideline recommended or – if not available – current medical standard. Weak recommendation, strong consensus (15/15; 10/10). Rationale: We are not aware of any interdisciplinary evidencebased guideline which recommends opioids as a first line treatment for any type of CNCP. Nonpharmacological therapies such as exercise and psychological therapies have been recommended as first line therapies for common CNCP syndromes such as low back (Oliveira etal.,2018) or osteoarthritis pain (Gay etal.,2016). Although nonpharmacological approaches for chronic pain have only small effect sizes with NNTs ranging from 4 to above 10 (Skelly etal.,2018), they should be optimized first given that the efficacy of drug therapies for CNCP syndromes such as low back pain is limited too and associated with potentially significant side effects. Anticonvulsants have been recommended as first line therapy for neuropathic pain (Finnerup et al., 2015). Potential serious adverse events such as overdose death and addiction by opioids (Busse et al., 2012), gastrointestinal bleeding (Castellsague et al., 2012) and cardiovascular events by NSAIDs (Bally etal., 2017), nonmedical use of gabapentinoids (Schjerning etal.,2016), and liver failure by antidepressants (Darr & Sussman,2020) must be considered. Evidence summary (for details see Supplementary Material 3): PICO (Patient, Intervention, Comparator, Outcome): What is the efficacy, tolerability and safety of opioids compared to nonopioid analgesics for CNCP in RCTs of at least 4weeks duration? A systematic review of RCTs comparing opioids with nonopioid analgesics found that nonopioid analgesics were superior to opioids in terms of improvement of physical function and tolerability in shortterm (4– 12weeks) therapy of neuropathic, low back and osteoarthritis pain (moderate quality UptoDate evidence) (Welsch etal.,2015). These results are in accordance with the findings of the recent review on behalf of the US Agency for Healthcare Research and Quality (Chou etal.,2020). 3. Selection of medications: The selection of medications should consider the type of CNCP, the comorbidities of the patient, contraindications, patient preferences, benefits and harms of previous therapies and the benefitrisk ratio of available pharmacological alternative treatment options. Good clinical practice statement. Strong Consensus (16/16; 11/11) Comment: There is marked interindividual variation in response/tolerability of all analgesics including various opioids that is not predicatable prospectively. A number of factors may influence the clinician's choice of opioid when initiating treatment including: • Clinician's preference, often based on familiarity, availability and cost • Required route of delivery – e.g. oral (preferrred) but in some instances a transdermal delivery may be selected for ease of administration and reducing oral medication burden etc. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 | 957 HÄUSER Et al. • Comorbidities of the patient (see section on special situations) 4. Potential indications Preliminary remarks: a. All potential indication cited below should only be considered in the view of the recommendations on the role of opioids in the management of CNCP. b. CNCP is a descriptive term which covers many painful medical conditions which vary in clinical presentation and underlying pathophysiological mechanisms, including the absence of identifiable underlying mechanism. The IASPWHO joint task force which developed the new concepts of the chronic pain classification system has suggested a distinction between chronic primary pain (disease of its own right) and chronic secondary pain (pain as a symptom of an underlying disease). The main pathophysiological mechanism of primary pain syndromes is nociplastic pain and of chronic secondary pain syndromes nociceptive and/or neuropathic pain (Nicholas etal.,2019; Treede etal.,2019; Trouvin & Perrot,2019). Nociplastic pain is defined by pain that (1) arises from altered nociception despite no (2) clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or (3) evidence for disease or lesion of the somatosensory system causing the pain (Kosek etal.,2016). The distinction between primary and secondary pain can be an oversimplification. In some patients with chronic secondary pain, such as osteoarthritis or postinjury pain, nociplastic mechanisms play a role (Moore etal.,2020; Woolf,1983). Ongoing nociceptive input, for example, by low grade joint inflammation, may play a role in socalled secondary (comorbid) fibromyalgia (Fitzcharles etal.,2018) which is regarded to be a prototype of a nociplastic pain syndrome (Nicholas etal.,2019). Because of the diversity of CNCP syndromes, the updated position paper follows the approach of the French and German guideline (Häuser et al., 2020; Moisset & Martinez,2016), to split CNCP into different clinical entities with regards to potential indications and contraindications of opioids. 4.1 We suggest considering opioids for the chronic secondary pain syndromes listed below. Weak recommendation Evidence summary (for details see Supplementary Material 4): PICO: What is the efficacy, tolerability and safety of opioids compared to placebo in patients of any age with CNCP? There is low to very low quality GRADE evidence from 21 RCTs of 4– 15weeks with 7,650 participants that opioids are superior in reducing pain and disability, inferior in tolerability and not different in safety compared to placebo for CLBP- pain (Petzke etal.,2020) (Supplementary Materials 1 and 2). There is low to very low quality GRADE evidence from 22 RCTs of 4– 26weeks with 8,942 participants that opioids are superior in reducing pain and disability, inferior in tolerability and not different in safety compared to placebo for OA- pain (Welsch etal.,2020). There is low to very low quality GRADE evidence from 16 RCTs of 4– 12weeks with 2,199 participants that opioids are superior in reducing pain and disability, inferior in tolerability and not different in safety compared to placebo for some neuropathic pain syndromes (Sommer etal.,2020). There is very low quality GRADE evidence from 15 open label extension studies of up to 4years duration with 3,590 participants that in selfselected patients with chronic low back, neuropathic and OA pain, reductions of pain and disability can be maintained. Drop out rate due to adverse events and deaths increase with study duration (Bialas etal.,2020). The low rate of serious adverse events in RCTs with opioids is in sharp contrast to the results of observational studies in North America which have demonstrated important risks of nonfatal and fatal unintentional overdose, very frequent physical dependence and frequent addiction (Busse et al., 2017). Routine clinical care data from some European countries did not show signals of an opioid epidemic (Bedene etal.,2019; Chenaf etal.,2019; Kalkman etal.,2019; Rosner etal.,2019). Potential explanations of these divergences are as follows: a. Most RCTs excluded patients with current or a history of substance abuse and with major medical diseases. These (relative) contraindications for opioids might have been neglected in routine medical care in North America. Opioids have been prescribed to the most vulnerable part of the population (unemployment, poverty, mental health problems) (deWeerdt, 2019). b. The surveillance of patients in the context of clinical studies is closer than the one in routine clinical care. c. There are differences in the health care systems between North America and Europe (e.g. availability of nonpharmacological treatments; expectations of patients to get medication prescription; financial benefits by increasing the number of patients by opioid prescriptions). d. Most RCTs did not systematically assess nonmedical use and dependence or opioid use disorder and therefore may have underestimated their prevalence. 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 964 | HÄUSER Et al. concluded from the strength of consensus separately assessed for the whole guideline group and the ones without financial COIs. CDC reviewed potential nonfinancial conflicts carefully (e.g. intellectual property, travel, public statements or positions such as congressional testimony) to determine if the activities would have a direct and predictable effect on the recommendation. Methods: All guidelines/recommendations conducted systematic searches of literature, performed metaanalyses of randomized placebocontrolled trials with opioids and rated the quality of evidence. The European guidelines assessed the strength of consensus on recommendations and clinical practice statements of the TF. EFIC's strong consensus for GCP and lack of strong consensus on most potential indications and contraindications reflect the different clinical background and experience with opioids for CNCP of the TF members. All guidelines/recommendations used GRADE to rate the quality of evidence for evidencebased recommendations. The majority of the European guidances for clinicians were based on a selective search of literature and expert consensus. Overall content: Canada produced 10, CDC 12 and Europe six evidencebased recommendations. Canada offered 10 evidence – based expert guidances and Europe 60 good clinical practice statements. Role of opioids in the management of CNCP: All guidelines/recommendations recommended to start a trial with opioids only if nonpharmacological and nonopioid medications have failed. The European recommendations specified that established (guidelinerecommended) treatments should have failed. The belief that opioids are the most powerful medication against CNCP have not been supported by any of the three guidelines, which demonstrated that opioids and nonopioid analgesics are equally effective in reducing pain (with small effect sizes). Therefore, the World Health Organization's analgesic ‘ladder’ for cancerpain treatment, which placed nonsteroidal antiinflammatory drugs (NSAIDs) on the bottom rung for mild pain and opioids on higher rungs for persistent moderate- to severe pain, is not supported in CNCP. In contrast to the North American guidelines, the European recommendations gave different recommendations for different types of CNCP, for example, not to treat primary chronic pain syndromes with opioids. Prescription of high doses of opioids to patients with primary pain syndromes might have been a factor driving the opioid crisis in North America. Inclusion of patients with physical and psychological trauma, social disadvantage, and hopelessness that can enhance reports of pain intensity may have also resulted in prescription of more opioids (Dasgupta etal.,2018; deWeerdt,2019; Petzke et al., 2020). All three papers defined stopping rules for opioid therapy. 5 | CONCLUSIONS Opioids are not a panacea for all types of CNCP, and must only be used in selected and supervised pain patients as part of a comprehensive, multimodal, multidisciplinary approach to treatment. In this context alone, opioid therapy can be a useful tool in achieving and maintaining an optimal level of pain control in selected patients. Misplaced barriers to access (e.g. payers restricting reimbursement or requiring previous authorizations that lead to lengthy delays) can lead to unnecessary suffering, just as overlyzealous prescription of opioids can lead to unnecessary suffering. As recently stated by Barnett (2020), “the opioidprescribing debate seems hopelessly polarized: either opioids are industrially sponsored weapons of mass addiction or they‘re a misunderstood last hope for alleviating suffering. The optimal use of medications lies between these two poles.” Opioids are a two edged sword. Used inappropriately (wrong indication, inappropriate monitoring of positive and negative effects, inadequate management of side effects) they can be associated with relevant harms to the patient. Therefore, the European Pain Federation calls for continuous medical education on the correct use of opioids in multiprofessional and multimodal therapeutic approaches. We also call for enhancing access to, and funding for, comprehensive pain treatment services and therapies and increasing funds for robust research in pain treatment. ACKNOWLEDGEMENTS The authors thank Sarah Badreh, Melinda Borzsak- Schramm, Christel Geevels and Sam Kynman (EFIC's executive office) for organizational support. CONFLICTS OF INTEREST Eric Buchser received research funding by Medtronic. Geert Dom received personal fees for advisory board activities by Janssen (Belgium). Asborn Drewes: received research grant by Grünenthal, personal fees for advisory board and/or speaker's activities by Kyowa- Kirin. Bart Morlion received grants and/or honoraria for clinical research by Novartis, Pfizer, Janssen, Shionogi; for speaker's activitiesby Grünenthal, Lilly, Mundipharma, Pfizer and for consultancy activities by Astellas, Boehringer Ingelheim, Grünenthal, Janssen, Mundipharma, TEVA, GSK, Kyowa- Kirin, Pfizer, Liilly, Boston Scientific, P&G. Tony O'Brien received an educational grant to Marymount University Hospital & Hospice in support of an international conference to celebrate the 150th anniversary of the foundation by Napp Educational Foundation and received personal fees (lectures) from Mundipharma, Kyowa Kirin and Shionogi Esther Pogatzi- Zahn received research grants by Grünenthal and Mundipharma and personal fees for advisory board and/ 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 | 965 HÄUSER Et al. or speaker's activities by MSD, ArcelRx, Janssen- Cilag and Fresenius Kabi. Thomas Tölle TT received honoraria for consultancies, travel grants and speaking fees for AOP Orphan, Almiral Hermal, Bionest Partners, Benkitt Renkiser, Grünenthal, Hexal, Indivior, Kaia Health, Lilly, Medscape, Mundipharma, MSD, Novartis, Pfizer, Recordati Pharma, Sanofi- Aventis, and TAD Pharma. The other authors have no financial conflicts of interest to declare. AUTHOR CONTRIBUTIONS WH performed the search of literature. All authors participated in developing the clinical practice recommendations. NKS, KV and WH wrote the manuscript. All authors discussed and commented on the manuscript. REFERENCES Agarwal, D., Udoji, M. A., & Trescot, A. (2017). Genetic testing for opioid pain management: A primer. Pain and Therapy, 6, 93– 105. https://doi.org/10.1007/s4012 2- 017- 0069- 2 Andrews, J. C., Schünemann, H. J., Oxman, A. D., Pottie, K., Meerpohl, J. J., Coello, P. A., Rind, D., Montori, V. M., Brito, J. P., Norris, S., Elbarbary, M., Post, P., Nasser, M., Shukla, V., Jaeschke, R., Brozek, J., Djulbegovic, B., & Guyatt, G. (2013). GRADE guidelines: 15. Going from evidence to recommendationdeterminants of a recommendation's direction and strength. Journal of Clinical Epidemiology, 66, 726– 735. https://doi.org/10.1016/j.jclin epi.2013.02.003 Ashina, S. (2019). Opioid use among people with migraine: Results of the OVERCOME study. Presented at: American Headache Society Annual Scientific Meeting; July 11– 14, Philadelphia. Ballantyne, J. C., & Sullivan, M. D. (2015). Intensity of chronic pain – The wrong metric? New England Journal of Medicine, 373, 2098– 2099. https://doi.org/10.1056/NEJMp 1507136 Ballantyne, J. C. (2016). Avoiding opioid analgesics for treatment of chronic low back pain. JAMA, 315, 2459– 2460. https://doi. org/10.1001/jama.2016.6753 Bally, M., Dendukuri, N., Rich, B., Nadeau, L., Helin- Salmivaara, A., Garbe, E., & Brophy, J. M. (2017). Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian metaanalysis of individual patient data. BMJ, 357, j1909. https://doi.org/10.1136/ bmj.j1909 Barnett, M. L. (2020). Opioid prescribing in the midst of crisis – Myths and realities. New England Journal of Medicine, 382, 1086– 1088. https://doi.org/10.1056/NEJMp 1914257 Bedene, A., Lijfering, W. M., Niesters, M., van Velzen, M., Rosendaal, F. R., Bouvy, M. L., Dahan, A., & van Dorp, E. L. A. (2019). Opioid prescription patterns and risk factors associated with opioid use in the Netherlands. JAMA Network Open, 2019(2), e1910223. https:// doi.org/10.1001/jaman etwor kopen.2019.10223 Bennett, M. I., Eisenberg, E., Ahmedzai, S. H., Bhaskar, A., O'Brien, T., Mercadante, S., Krčevski Škvarč, N., Vissers, K., Wirz, S., Wells, C., & Morlion, B. (2019). Standards for the management of cancerrelated pain across Europe- A position paper from the EFIC Task Force on Cancer Pain. European Journal of Pain, 23, 660– 668. https://doi.org/10.1002/ejp.1346 Bennett, R. M., Kamin, M., Karim, R., & Rosenthal, N. (2003). Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: A doubleblind, randomized, placebocontrolled study. American Journal of Medicine, 114, 537– 545. https://doi. org/10.1016/S0002 - 9343(03)00116 - 5 Bialas, P., Maier, C., Klose, P., & Häuser, W. (2020). Efficacy and harms of longterm opioid therapy in chronic noncancer pain: Systematic review and metaanalysis of openlabel extension trials with a study duration ≥26 weeks. European Journal of Pain, 24, 265– 278. https://doi.org/10.1002/ejp.1496 Bilal, M., Chatila, A., Siddiqui, M. T., Al- Hanayneh, M., Shah, A. R., Desai, M., Wadhwa, V., Parupudi, S., Casey, B. W., Krishnan, K., & Hernandez- Barco, Y. G. (2019). Rising prevalence of opioid use disorder and predictors for opioid use disorder among hospitalized patients with chronic pancreatitis. Pancreas, 48, 1386– 1392. https:// doi.org/10.1097/MPA.00000 00000 001430 Bruera, E., Macmillan, K., Hanson, J., & MacDonald, R. N. (1989). The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain, 39, 13– 16. https://doi. org/10.1016/0304- 3959(89)90169 - 3 Burr, N. E., Smith, C., West, R., Hull, M. A., & Subramanian, V. (2018). Increasing prescription of opiates and mortality in patients with inflammatory bowel diseases in England. Clinical Gastroenterology and Hepatology, 16, 534– 54.1. Busse, J. W., Craigie, S., Juurlink, D. N., Buckley, D. N., Wang, L., Couban, R. J., Agoritsas, T., Akl, E. A., Carrasco- Labra, A., Cooper, L., Cull, C., da Costa, B. R., Frank, J. W., Grant, G., Iorio, A., Persaud, N., Stern, S., Tugwell, P., Vandvik, P. O., … Calingaert, B. (2012). Individual NSAIDs and upper gastrointestinal complications: A systematic review and metaanalysis of observational studies (the SOS project). Drug Safety, 35, 1127– 1146. https://doi. org/10.1007/BF032 61999 Busse, J. W., Craigie, S., Juurlink, D. N., Buckley, D. N., Wang, L., Couban, R. J., Agoritsas, T., Akl, E. A., Carrasco- Labra, A., Cooper, L., Cull, C., da Costa, B. R., Frank, J. W., Grant, G., Iorio, A., Persaud, N., Stern, S., Tugwell, P., Vandvik, P. O., & Guyatt, G. H. (2017). Guideline for opioid therapy and chronic noncancer pain. Canadian Medical Association Journal, 189, E659– E666. Castellsague, J., Riera- Guardia, N., Calingaert, B., Varas- Lorenzo, C., Fourrier- Reglat, A., Nicotra, F., Sturkenboom, M., & Perez- Gutthann, S. (2012). Safety of Non- Steroidal Anti- Inflammatory Drugs (SOS) Project. Individual NSAIDs and upper gastrointestinal complications: a systematic review and metaanalysis of observational studies (the SOS project). Drug Safety, 35, 1127– 46. Chenaf, C., Kaboré, J. L., Delorme, J., Pereira, B., Mulliez, A., Zenut, M., Delage, N., Ardid, D., Eschalier, A., & Authier, N. (2019). Prescription opioid analgesic use in France: Trends and impact on morbiditymortality. European Journal of Pain, 23, 124– 134. https://doi.org/10.1002/ejp.1291 Chou, R., Deyo, R., Friedly, J., Skelly, A., Weimer, M., Fu, R., Dana, T., Kraegel, P., Griffin, J., & Grusing, S. (2017). Systemic pharmacologic therapies for low back pain: A systematic review for an American College of Physicians Clinical Practice Guideline. Annals of Internal Medicine, 166, 480– 492. https://doi.org/10.7326/M16- 2458 Chou, R., Hartung, D., Turner, J., Blazina, I., Chan, B., Levander, X., McDonagh, M., Selph, S., Fu, R., & Pappas, M. (2020). Opioid treatments for chronic pain. Agency for Healthcare Research and Quality (US). Coates, M. D., Seth, N., Clarke, K., Abdul- Baki, H., Mahoney, N., Walter, V., Regueiro, M. D., Ramos- Rivers, C., Koutroubakis, I. E., Bielefeldt, K., & Binion, D. G. (2020). Opioid analgesics do not improve abdominal pain or quality of life in Crohn's disease. Digestive 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 966 | HÄUSER Et al. Diseases and Sciences, 65(8), 2379– 2387. https://doi.org/10.1007/ s1062 0- 019- 05968 - x Cragg, A., Hau, J. P., Woo, S. A., Kitchen, S. A., Liu, C., Doyle- Waters, M. M., & Hohl, C. M. (2019). Risk factors for misuse of prescribed opioids: A systematic review and metaanalysis. Annals of Emergency Medicine, 74, 634– 646. https://doi.org/10.1016/j.annem ergmed.2019.04.019 Darr, U., & Sussman, N. L. (2020). Druginduced liver injury in the setting of analgesic use. Clinics in Liver Disease, 2020(24), 121– 129. https://doi.org/10.1016/j.cld.2019.09.008 Dasgupta, N., Beletsky, L., & Ciccarone, D. (2018). Opioid crisis: No easy fix to its social and economic determinants. American Journal of Public Health, 108, 182– 186. https://doi.org/10.2105/ AJPH.2017.304187 DeWeerdt, S. (2019). Tracing the US opioid crisis to its roots. Nature, 573, S10– S12. https://doi.org/10.1038/d4158 6- 019- 02686 - 2 Dowell, D., Haegerich, T. M., & Chou, R. (2016). CDC guideline for prescribing opioids for chronic pain– United States, 2016. JAMA, 315, 1624– 1645. https://doi.org/10.1001/jama.2016.1464 Drewes, A. M., Jensen, R. D., Nielsen, L. M., Droney, J., Christrup, L. L., Arendt- Nielsen, L., Riley, J., & Dahan, A. (2013). Differences between opioids: Pharmacological, experimental, clinical and economical perspectives. British Journal of Clinical Pharmacology, 75, 60– 78. Drewes, A. M., Bouwense, S. A. W., Campbell, C. M., Ceyhan, G. O., Delhaye, M., Demir, I. E., Garg, P. K., van Goor, H., Halloran, C., Isaji, S., Neoptolemos, J. P., Olesen, S. S., Palermo, T., Pasricha, P. J., Sheel, A., Shimosegawa, T., Szigethy, E., Whitcomb, D. C., & Yadav, D. (2017). Guidelines for the understanding and management of pain in chronic pancreatitis. Pancreatology, 17, 720– 731. https:// doi.org/10.1016/j.pan.2017.07.006 Farmer, A. D., Drewes, A. M., Chiarioni, G., De Giorgio, R., O'Brien, T., Morlion, B., & Tack, J. (2019). Pathophysiology and management of opioidinduced constipation: European expert consensus statement. United European Gastroenterology Journal, 7, 7– 20. https://doi.org/10.1177/20506 40618 818305 Finnerup, N. B., Attal, N., Haroutounian, S., McNicol, E., Baron, R., Dworkin, R. H., Gilron, I., Haanpää, M., Hansson, P., Jensen, T. S., Kamerman, P. R., Lund, K., Moore, A., Raja, S. N., Rice, A. S. C., Rowbotham, M., Sena, E., Siddall, P., Smith, B. H., & Wallace, M. (2015). Pharmacotherapy for neuropathic pain in adults: A systematic review and metaanalysis. The Lancet Neurology, 14, 162– 173. https://doi.org/10.1016/S1474 - 4422(14)70251 - 0 Fitzcharles, M. A., Faregh, N., Ste- Marie, P. A., & Shir, Y. (2013). Opioid use in fibromyalgia is associated with negative health related measures in a prospective cohort study. Pain Res Treat, 2013, 898493. https://doi.org/10.1155/2013/898493 Fitzcharles, M. A., Perrot, S., & Häuser, W. (2018). Comorbid fibromyalgia: A qualitative review of prevalence and importance. European Journal of Pain, 22, 1565– 1576. https://doi.org/10.1002/ ejp.1252 Furlan, A. D., Reardon, R., & Weppler, C.; National Opioid Use Guideline Group. (2010). Opioids for chronic noncancer pain: A new Canadian practice guideline. Canadian Medical Association Journal, 182, 923– 930. https://doi.org/10.1503/cmaj.100187 Gay, C., Chabaud, A., Guilley, E., & Coudeyre, E. (2016). Educating patients about the benefits of physical activity and exercise for their hip and knee osteoarthritis. Systematic literature review. Annals of Physical and Rehabilitation Medicine, 59, 174– 183. https://doi. org/10.1016/j.rehab.2016.02.005 Goshua, A., Craigie, S., Guyatt, G. H., Agarwal, A., Li, R., Bhullar, J. S., Scott, N., Chahal, J., Pavalagantharajah, S., Chang, Y., Couban, R., & Busse, J. W. (2018). Patient values and preferences regarding opioids for chronic noncancer pain: A systematic review. Pain Medicine, 19, 2469– 2480. https://doi.org/10.1093/pm/pnx274 Häuser, W., Buchser, E., Finn, D., Dom, G., Fors, E., Heiskanen, T., Jarlbaek, L., Knaggs, R. D., Kosek, E., Krcevski- Škvarč, N. J., Pakkonen, K., Perrot, S. D., Trouvain, A. P., & Morlion, M. (2021). Is Europe also facing an opioid crisis – A narrative review and survey of European Pain Federation chapters. European Journal of Pain (submitted). Häuser, W., Bock, F., Hüppe, M., Nothacker, M., Norda, H., Radbruch, L., Schiltenwolf, M., Schuler, M., Tölle, T., Viniol, A., & Petzke, F.; Koautoren für die Konsensusgruppe der 2. Aktualisierung der S3- Leitlinie LONTS. (2020). Recommendations of the second update of the LONTS guidelines: Longterm opioid therapy for chronic noncancer pain. Schmerz, 34, 204– 244. Kaiser, U., Treede, R. D., & Sabatowski, R. (2017). Multimodal pain therapy in chronic noncancer paingold standard or need for further clarification? Pain, 158, 1853– 1859. https://doi.org/10.1097/j. pain.00000 00000 000902 Kalkman, G. A., Kramers, C., van Dongen, R. T., van den Brink, W., & Schellekens, A. (2019). Trends in use and misuse of opioids in the Netherlands: A retrospective, multisource database study. Lancet Public Health, 4, e498– e505. Karmali, R. N., Bush, C., Raman, S. R., Campbell, C. I., Skinner, A. C., & Roberts, A. W. (2020). Longterm opioid therapy definitions and predictors: A systematic review. Pharmacoepidemiology and Drug Safety, 29, 252– 269. https://doi.org/10.1002/pds.4929 Kosek, E., Cohen, M., Baron, R., Gebhart, G. F., Mico, J. A., Rice, A. S., Rief, W., & Sluka, A. K. (2016). Do we need a third mechanistic descriptor for chronic pain states? Pain, 157, 1382– 1386. https://doi. org/10.1097/j.pain.00000 00000 000507 Krcevski- Škvarc, N., Morlion, B., Vowles, K. E., Bannister, K., Buchsner, E., Casale, R., Chenot, F.- C., Chumbley, G., Drewes, A. M., Dom, G., Jutila, L., O'Brien, T., Pogatzky- Zahn, E., Ragusa, M., Suarez- Serrano, C., Tölle, T., & Häuser, W. (2021). European* clinical practice recommendations on opioids for chronic noncancer pain – Part 2. European Journal of Pain, in press. Langendam, M. W., Akl, E. A., Dahm, P., Glasziou, P., Guyatt, G., & Schünemann, H. J. (2013). Assessing and presenting summaries of evidence in Cochrane Reviews. Systematic Reviews, 2, 81. https:// doi.org/10.1186/2046- 4053- 2- 81 Lamb, C. A., Kennedy, N. A., Raine, T., Hendy, P. A., Smith, P. J., Limdi, J. K., Hayee, B. H., Lomer, M. C. E., Parkes, G. C., Selinger, C., Barrett, K. J., Davies, R. J., Bennett, C., Gittens, S., Dunlop, M. G., Faiz, O., Fraser, A., Garrick, V., Johnston, P. D., … Hawthorne, A. B. (2019). British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut, 68(Suppl 3), s1– s106. https://doi.org/10.1136/gutjn l- 2019- 318484 Macfarlane, G. J., Kronisch, C., Dean, L. E., Atzeni, F., Häuser, W., Fluß, E., Choy, E., Kosek, E., Amris, K., Branco, J., Dincer, F., Leino- Arjas, P., Longley, K., McCarthy, G. M., Makri, S., Perrot, S., Sarzi- Puttini, P., Taylor, A., & Jones, G. T. (2017). EULAR revised recommendations for the management of fibromyalgia. Annals of the Rheumatic Diseases, 76, 318– 328. https://doi.org/10.1136/annrh eumdi s- 2016- 209724 Maher, C., Underwood, M., & Buchbinder, R. (2017). Nonspecific low back pain. Lancet, 389, 736– 747. https://doi.org/10.1016/S0140 - 6736(16)30970 - 9 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 | 967 HÄUSER Et al. Minen, M. T., Tanev, K., & Friedman, B. W. (2014). Evaluation and treatment of migraine in the emergency department: A review. Headache: the Journal of Head and Face Pain, 54, 1131– 1145. https://doi.org/10.1111/head.12399 Moisset, X., & Martinez, V. (2016). Opioid use for the management of chronic noncancer pain: French guidelines. Revue Neurologique, 172, 337– 338. https://doi.org/10.1016/j.neurol.2016.05.004 Moore, A. R., Eccleston, C., Derry, S., Wiffen, P., Bell, R. F., Straube, S., & McQuay, H. (2010). “Evidence” in chronic painestablishing best practice in the reporting of systematic reviews. Pain, 150, 386– 389. https://doi.org/10.1016/j.pain.2010.05.011 Moore, R., Clifford, A. M., Moloney, N., Doody, C., Smart, K. M., & O'Leary, H. (2020). The relationship between clinical and quantitative measures of pain sensitization in knee osteoarthritis. Clinical Journal of Pain, 36, 336– 343. https://doi.org/10.1097/AJP.00000 00000 000798 Niemann, T., Madsen, L. G., Larsen, S., & Thorsgaard, N. (2000). Opioid treatment of painful chronic pancreatitis. International Journal of Pancreatology, 27, 235– 240. Nicholas, M., Vlaeyen, J. W. S., Rief, W., Barke, A., Aziz, Q., Benoliel, R., Cohen, M., Evers, S., Giamberardino, M. A., Goebel, A., Korwisi, B., Perrot, S., Svensson, P., Wang, S. J., & Treede, R. D. (2019). The IASP Taskforce for the Classification of Chronic pain. The IASP classification of chronic pain for ICD- 11: Chronic primary pain. Pain, 160, 28– 37. https://doi.org/10.1097/j.pain.00000 00000 001390 O'Brien, T., Christrup, L. L., Drewes, A. M., Fallon, M. T., Kress, H. G., McQuay, H. J., Mikus, G., Morlion, B. J., Perez- Cajaraville, J., Pogatzki- Zahn, E., Varrassi, G., & Wells, J. C. (2017). European Pain Federation position paper on appropriate opioid use in chronic pain management. European Journal of Pain, 21, 3– 19. Olesen, S. S., Nøjgaard, C., Poulsen, J. L., Haas, S. L., Vujasinovic, M., Löhr, M., Lindkvist, B., Bexander, L., Gulbinas, A., Kalaitzakis, E., Ebrahim, M., Erchinger, F., Engjom, T., Roug, S., Novovic, S., Hauge, T., Waage, A., Laukkarinen, J., Parhiala, M., … Drewes, A. M.; Scandinavian Baltic Pancreatic Club. (2019). Chronic pancreatitis is characterized by distinct complication clusters that associate with etiological risk factors. American Journal of Gastroenterology, 114, 656– 664. https://doi.org/10.14309/ ajg.00000 00000 000147 Olesen, S. S., Nøjgaard, C., Novovic, S., Jensen, N. M., Nørregaard, P., Dahl, E. E., Waage, A., Hauge, T., Barauskas, G., Parhiala, M., Laukkarinen, J., & Drewes, A. M. (2020). Pain and aetiological risk factors determine quality of life in patients with chronic pancreatitis, but a brick in the puzzle is missing. Pancreatology, 20(7), 30704– 30713. https://doi.org/10.1016/j.pan.2020.09.004 Oliveira, C. B., Maher, C. G., Pinto, R. Z., Traeger, A. C., Lin, C.- W., Chenot, J.- F., van Tulder, M., & Koes, B. W. (2018). Clinical practice guidelines for the management of nonspecific low back pain in primary care: An updated overview. European Spine Journal, 27, 2791– 2803. https://doi.org/10.1007/s0058 6- 018- 5673- 2 Petzke, F., Klose, P., Welsch, P., Sommer, C., & Häuser, W. (2020). Opioids for chronic low back pain: An updated systematic review and metaanalysis of efficacy, tolerability and safety in randomized placebocontrolled studies of at least 4 weeks of doubleblind duration. European Journal of Pain, 24, 497– 517. https://doi. org/10.1002/ejp.1519 Ranapurwala, S. I., Naumann, R. B., Austin, A. E., Dasgupta, N., & Marshall, S. W. (2019). Methodologic limitations of prescription opioid safety research and recommendations for improving the evidence base. Pharmacoepidemiology and Drug Safety, 28, 4– 12. https://doi.org/10.1002/pds.4564 Rosner, B., Neicun, J., Yang, J. C., & Roman- Urrestarazu, A. (2019). Opioid prescription patterns in Germany and the global opioid epidemic: Systematic review of available evidence. PLoS One, 14, e0221153. https://doi.org/10.1371/journ al.pone.0221153 Russell, I. J., Kamin, M., Bennett, R. M., Schnitzer, T. J., Green, J. A., & Katz, W. A. (2000). Efficacy of tramadol in treatment of pain in fibromyalgia. Journal of Clinical Rheumatology, 6, 250– 257. https:// doi.org/10.1097/00124 743- 20001 0000- 00004 Schjerning, O., Rosenzweig, M., Pottegård, A., Damkier, P., & Nielsen, J. (2016). Abuse potential of pregabalin: A systematic review. CNS Drugs, 30, 9– 25. https://doi.org/10.1007/s4026 3- 015- 0303- 6 Skelly, A. C., Chou, R., & Dettori, J. R. (2018). Noninvasive nonpharmacological treatment for chronic pain: A systematic review. Agency for Healthcare Research and Quality (US). Sommer, C., Klose, P., Welsch, P., Petzke, F., & Häuser, W. (2020). Opioids for chronic noncancer neuropathic pain. An updated systematic review and metaanalysis of efficacy, tolerability and safety in randomized placebocontrolled studies of at least 4 weeks duration. European Journal of Pain, 24, 3– 18. https://doi.org/10.1002/ ejp.1494 Sullivan, M. D., & Howe, C. Q. (2013). Opioid therapy for chronic pain in the United States: Promises and perils. Pain, 154(Suppl 1), S94– S100. https://doi.org/10.1016/j.pain.2013.09.009 Toubia, T., & Khalife, T. (2019). The endogenous opioid system: Role and dysfunction caused by opioid therapy. Clinical Obstetrics and Gynecology, 62, 3– 10. https://doi.org/10.1097/GRF.00000 00000 000409 Treede, R. D., Rief, W., Barke, A., Aziz, Q., Bennett, M. I., Benoliel, R., Cohen, M., Evers, S., Finnerup, N. B., First, M. B., Giamberardino, M. A., Kaasa, S., Korwisi, B., Kosek, E., Lavandʼhomme, P., Nicholas, M., Perrot, S., Scholz, J., Schug, S., … Wang, S. J. (2019). Chronic pain as a symptom or a disease: The IASP Classification of Chronic Pain for the International Classification of Diseases (ICD- 11). Pain, 160, 19– 27. https://doi.org/10.1097/j.pain.00000 00000 001384 Treillet, E., Laurent, S., & Hadjiat, Y. (2018). Practical management of opioid rotation and equianalgesia. Journal of Pain Research, 11, 2587– 2601. Trouvin, A. P., & Perrot, S. (2019). New concepts of pain. Best Practice & Research Clinical Rheumatology, 33, 01415. Walitt, B., Klose, P., Fitzcharles, M. A., Phillips, T., & Häuser, W. (2016). Cannabinoids for fibromyalgia. Cochrane Database Systematic Review, 7, CD011694. https://doi.org/10.1002/14651 858.CD011 694.pub2 Welsch, P., Sommer, C., Schiltenwolf, M., & Häuser, W. (2015). Opioids in chronic noncancer painare opioids superior to nonopioid analgesics? A systematic review and metaanalysis of efficacy, tolerability and safety in randomized head- to- head comparisons of opioids versus nonopioid analgesics of at least four week's duration. Schmerz, 29, 85– 95. Welsch, P., Petzke, F., Klose, P., & Häuser, W. (2020). Opioids for chronic osteoarthritis pain: An updated systematic review and metaanalysis of efficacy, tolerability and safety in randomized placebocontrolled studies of at least 4 weeks doubleblind duration [published correction appears in Eur J Pain, 24; 1420]. European Journal of Pain, 24, 685– 703. Wiffen, P. J., Wee, B., Derry, S., Bell, R. F., & Moore, R. A. (2017). Opioids for cancer pain – An overview of Cochrane reviews. Cochrane Database Systematic Review, 7, CD012592. Woolf, C. J. (1983). Evidence for a central component of postinjury pain hypersensitivity. Nature, 306, 686– 688. https://doi. org/10.1038/306686a0 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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 968 | HÄUSER Et al. Zaccara, G., Gangemi, P., Perucca, P., & Specchio, L. (2011). The adverse event profile of pregabalin: A systematic review and metaanalysis of randomized controlled trials. Epilepsia, 52, 826– 836. https://doi.org/10.1111/j.1528- 1167.2010.02966.x WEB REFERENCES American Headache Society. (2019). Opioids and migraine. Retrieved from https://ameri canhe adach esoci ety.org/news/opioi dsmigra ine/ Drossman, D. (2019). Understanding and managing pain in irritable bowel syndrome. Retrieved from https://www.about ibs.org/under stand ing- and- manag ingpain- inibs.html?showa ll=1 European Medicines Agency. (2017). Guideline on the clinical development of medicinal products intended for the treatment of pain. Retrieved from https://www.ema.europa.eu/en/clini caldevel opmen tmedic inalprodu ctsinten dedtreat mentpain National Records of Scotland. (2018). Drugrelated deaths in Scotland. Retrieved from https://www.nrsco tland.gov.uk/stati stics - anddata/ stati stics/ stati stics - bytheme/ vital - event s/death s/drugrelat eddeath sin- scotland Ramaekers, J., Knonche, A., & Schulze, H. (2006). Effects of medicinal drugs on actual and simulated driving. Retrieved from https://www. bast.de/Druid/ EN/deliv erale slist/downl oads/Deliv erable_1_2_2. pdf?__blob=publi catio nFile &v=1 UptoDate. (2020a). Grading tutorial. Retrieved from https://www.uptod ate.com/home/gradi ngtutorial UptoDate. (2020b). Management of short bowel syndrome. Retrieved from https://www.uptod ate.com/conte nts/manag ement - ofthe- short - bowel - syndr omein- adult s#H2670 286206 SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Häuser W, Morlion B, Vowles KE, et al. European clinical practice recommendations on opioids for chronic noncancer pain – Part 1: Role of opioids in the management of chronic noncancer pain. Eur J Pain. 2021;25:949– 968. https://doi.org/10.1002/ejp.1736 15322149, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1736 by Readcube (Labtiva Inc.), Wiley Online Library on [28/11/2024]. 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