French National Guidelines for the Appropriate Use of Opioids: Analgesia, Opioid Use Disorder, and Overdose Prevention-Part 1: Methodology and Pain Management

The increasing prescription of opioids worldwide has raised major safety concerns, highlighting the need for comprehensive, evidence-based guidelines grounded in the strongest available scientific evidence. These guidelines provide unified guidance covering the entire opioid pharmacological class. In acute pain, opioid use should be restricted to clearly defined situations, prescribed for the shortest possible duration, and combined with non-opioid strategies. In chronic non-cancer pain, long-term opioid therapy carries significant risks and should be reserved for carefully selected patients after thorough evaluation and under close monitoring. In cancer-related pain, opioids remain essential, with detailed guidance on titration, equianalgesic conversion, and prevention of adverse effects to ensure safe and effective use.

The guideline development process was based on a systematic literature review conducted by the French National Authority for Health (Haute Autorité de Santé [HAS]). The search covered clinical practice guidelines, systematic reviews, meta-analyses, randomized or controlled trials, and observational studies published between January 2009 and December 2021. Literature was accessed through PubMed, Embase, the Cochrane Library, and major guideline repositories. The list of websites consulted (publishing clinical guidelines, health technology assessments, ethical or economic reports, and professional society recommendations) is provided in Table S3 (Supplementary Material). Full details of the search strategy and selection process are available in Appendix 2 (Supplementary Material) and in the HAS guidance document “Development of Clinical Practice Guidelines – Method for Clinical Practice Recommendations [ 13 ].” To reduce the incidence of opioid overdose, physical dependence, and OUD, the objectives of these guidelines are to: - Reiterate the general principles governing the use of opioid medications. - Promote the appropriate use of opioid analgesics for acute and chronic pain, both cancer-related and non-cancer-related, in patients aged over 15 years. - Promote the appropriate use of OAT and naloxone for the prevention and management of OUD and overdoses. Reiterate the general principles governing the use of opioid medications. Promote the appropriate use of opioid analgesics for acute and chronic pain, both cancer-related and non-cancer-related, in patients aged over 15 years. Promote the appropriate use of OAT and naloxone for the prevention and management of OUD and overdoses. These guidelines apply to patients over 15 years of age treated with opioid analgesics for acute or chronic pain, cancer-related or non-cancer-related. They also apply to patients receiving OAT for physical dependence, as well as those with physical dependence and/or OUD related to prescribed or illicit opioids. The guidelines are intended for all healthcare professionals involved in the care of patients treated with opioid medications and/or presenting with OUD. This includes professionals working in outpatient or inpatient settings, in primary or secondary care, in social and medico-social institutions, as well as in prison healthcare units. The HAS, an independent public body with a scientific mandate, aims to improve the quality of healthcare and social services for the benefit of patients. In this context, it was tasked with developing national guidelines to enhance professional practices concerning the appropriate use of opioid medications. This mandate encompassed both their role in pain management and the prevention and management of OUD and overdoses, through the development of evidence-based national recommendations using a formal consensus method [ 13 ]. The detailed implementation procedures are provided in Appendix 2 (Supplementary Material). These guidelines were developed in accordance with the methodology outlined in the HAS manual Development of Clinical Practice Guidelines [ 13 ]. This process is rigorous and transparent, ensuring independence and appropriate management of potential conflicts of interest. A multidisciplinary working group (27 members, including healthcare professionals, patient representatives, and public agencies) conducted a systematic literature review (2009–2021, 4,453 references), resulting in the selection of 223 high-level evidence sources. Based on this review, a first draft of the guidelines was prepared and submitted to an extended reading group (49 members) for evaluation of clarity and applicability. Their feedback was incorporated into the final recommendations and summary sheets, which were validated by the HAS College and published in March 2022. These guidelines are based on previously conducted studies and existing recommendations and do not contain any new studies involving human participants or animals performed by any of the authors. These recommendations are primarily based on high-level evidence (including systematic reviews, meta-analyses, and randomized controlled trials) when available and are complemented by expert consensus in areas where evidence is limited.

Pain is common in cancer patients, particularly in advanced stages, and is one of the four essential components of supportive oncology care to which every patient is entitled [ 138 ]. During the curative phase, 30–50% of patients experience moderate to severe pain (≥ 5/10 on a numerical rating scale), rising to 50–60% in advanced cancer and 25% in remission. A neuropathic component is present in 20–40% of patients with active cancer and 20–30% of those in remission [ 139 ]. Breakthrough cancer pain (BTcP), defined as transient, short-lasting exacerbations of moderate to severe pain, affects approximately 68% of patients, according to a landmark study conducted by the European Association for Palliative Care [ 140 ]. BTcP occurs despite a background pain being controlled with strong opioids [ 141 ]. Although cancer-related pain can generally be relieved, some syndromes remain refractory to usual treatments. An estimated 10–18% of patients with active cancer and 10–20% of those in remission experience complex pain despite first-line pharmacological management [ 139 ]. Accurate identification of pain and etiology is crucial for effective management. Multimodal analgesia combined with etiological treatment forms the cornerstone of care. Opioids are indicated for the symptomatic treatment of nociceptive cancer pain, which often presents as mixed pain with a neuropathic component [ 142 ]. However, etiological treatment should always be prioritized, without delaying symptomatic management [ 143 ]. International, European, and French guidelines provide the framework for opioid use in this context and are detailed in the following sections. Psychological, social, and family assessment is crucial, given the multifactorial nature of pain. Systematic screening for anxiety, depression, and cognitive disorders is recommended, notably using the Hospital Anxiety and Depression Scale (HADS), which has been validated in cancer patients [ 144 , 145 ]. Psychological distress should be assessed and managed appropriately [ 143 ]. Pain evaluation should include an analysis of intensity, etiology, and pathophysiology, as well as the patient’s expectations regarding pain relief and functional recovery [ 142 ]. When initiating analgesic treatment, the following objectives should be pursued [ 144 ]: Minimal or absent background pain. Preserved sleep. Fewer than four BTcP episodes per day. Effective relief of BTcP in more than 50% of episodes. Daily activities maintained or minimally limited; in children, the ability to eat, move, and play must be preserved. Treatment-related adverse effects are minor or absent. Minimal or absent background pain. Preserved sleep. Fewer than four BTcP episodes per day. Effective relief of BTcP in more than 50% of episodes. Daily activities maintained or minimally limited; in children, the ability to eat, move, and play must be preserved. Treatment-related adverse effects are minor or absent. Pharmacological management of nociceptive cancer pain still follows the WHO three-step ladder (1985) [ 12 ]: step 1 non-opioid analgesics, step 2 “weak” opioids, and step 3 “strong” opioids, with systematic use of adjuvant drugs at each level. Key principles of the WHO approach remain valid [ 140 , 143 , 146 ]: Prefer oral administration. Prescribe at fixed intervals. Tailor therapy to individual needs. Ensure clear, detailed prescriptions. Prefer oral administration. Prescribe at fixed intervals. Tailor therapy to individual needs. Ensure clear, detailed prescriptions. Treatment must be continuously adjusted to the patient’s clinical situation, including pain etiology, age, comorbidities, and potential adverse effects [ 140 , 143 ]. Prescriptions should be understandable to patients and anticipate both predictable and unpredictable breakthrough pain. Reassessment should be aligned with the drug’s duration of action, formulation, and pain intensity [ 140 , 143 ]. Although the WHO analgesic ladder remains validated in cancer pain [ 12 ], it is increasingly complemented or replaced by more individualized approaches, including the Lussier and Beaulieu model [ 11 ]. In current clinical practice, treatment decisions are guided not only by pain intensity but also by the underlying pain mechanisms (nociceptive, neuropathic, nociplastic, or mixed) and patient-specific factors. In patients with cancer pain, strict adherence to a stepwise escalation is not always required, and step III opioids may be considered earlier in selected patients with severe pain when clinically justified [ 140 , 147 ]. Before initiating opioid therapy, a thorough pain assessment is required, considering pain intensity, previous analgesic treatments, and the patient’s overall clinical status [ 142 ]. The starting dose, administration frequency, and titration should be individualized to optimize the benefit–risk ratio [ 142 ]. For baseline analgesia (excluding rescue doses), combining different opioids, whether strong or weak, is generally not recommended [ 148 ]. Fixed-dose combinations of codeine/acetaminophen, tramadol/acetaminophen, or opium/acetaminophen require caution to avoid excessive acetaminophen intake, either from self-medication or concomitant prescriptions, which can lead to overdose and hepatotoxicity. Recommended maximum daily doses are 360 mg for codeine, 400 mg for tramadol, and 240 mg for dihydrocodeine [ 140 ]. In some cases of mild-to-moderate pain, low doses of Step III opioids (≤ 30 mg/day oral morphine, ≤ 20 mg/day oral oxycodone) may be used instead of high doses of Step II opioids [ 140 , 143 ]. The oral route is preferred [ 140 , 143 ]. Initiation: Step III opioid can be started with morphine or oxycodone, either as immediate-release or extended-release formulations [ 140 , 149 ]. Rescue doses of immediate-release opioids should always be prescribed, repeatable every hour if needed, with a maximum of six doses per day [ 140 , 143 ]. Each rescue dose should correspond to one-tenth to one-sixth of the 24-h total dose [ 140 , 143 ]. The cumulative rescue dose can then guide adjustment of the extended-release opioid dose [ 143 ]. Transdermal fentanyl may be considered in certain clinical contexts [ 140 , 143 ]: When rapid titration is not required. If the oral route is not feasible (e.g., intractable nausea and vomiting). In cases of risk of occlusion and/or malabsorption (fistulas, radiation enteritis, mutilating digestive surgery, severe diarrhea, etc.). In chronic renal failure. In patients with poor adherence. When rapid titration is not required. If the oral route is not feasible (e.g., intractable nausea and vomiting). In cases of risk of occlusion and/or malabsorption (fistulas, radiation enteritis, mutilating digestive surgery, severe diarrhea, etc.). In chronic renal failure. In patients with poor adherence. Intravenous titration is recommended when rapid pain control is required. Patient-controlled analgesia (PCA) can be considered if the patient is capable of self-administering boluses [ 140 ]. The subcutaneous route is also an option, though effectiveness may be reduced in patients with impaired absorption (malnutrition, edema, microcirculatory disorders) [ 140 , 143 , 147 ]. For painful procedures, immediate-release, short half-life opioids can be administered preventively [ 140 ]. For short-lasting pain (< 1h30) with rapid onset, when background opioid therapy is unsuitable or associated with intolerable adverse effects, transmucosal fentanyl may be considered (off-label use), starting with the lowest available dose of the chosen formulation [ 148 ]. In very exceptional cases, transmucosal fentanyl may also be used in patients experiencing only breakthrough pain episodes without underlying baseline pain requiring continuous therapy [ 148 ]. Safety consideration: Transmucosal fentanyl must always be administrated under direct supervision of a healthcare professional. Close monitoring during and after administration is mandatory to ensure safe use, given the high risk of respiratory depression. Supervision time should be adequate, and populations most vulnerable to respiratory depression should not receive transmucosal fentanyl [ 148 ]. In elderly patients, opioid doses should be reduced and/or dosing intervals increased [ 140 , 143 ]. Moderate renal impairment is not a contraindication to opioid therapy for cancer pain [ 140 ]. However, prolonged-release formulations should be avoided, and dosages adjusted by reducing the amount and/or extending dosing intervals [ 140 , 143 , 147 ]. Fentanyl and buprenorphine are preferred in this context [ 143 ]. Methadone, which has no active metabolites, can also be used safely [ 150 , 151 ]. In patients with hepatic impairment, opioids should be prescribed cautiously, considering [ 143 ]: The opioid’s primary metabolic pathway and active metabolites. Use of immediate-release oral or parenteral forms for treatment initiation. Starting at half doses or lower, depending on severity and metabolic pathway. Careful titration, adjusting subsequent dosing intervals and amounts based on the efficacy and duration of the first dose. After stabilization over several days, a prolonged-release formulation may be considered, with additional rescue doses if needed. The opioid’s primary metabolic pathway and active metabolites. Use of immediate-release oral or parenteral forms for treatment initiation. Starting at half doses or lower, depending on severity and metabolic pathway. Careful titration, adjusting subsequent dosing intervals and amounts based on the efficacy and duration of the first dose. After stabilization over several days, a prolonged-release formulation may be considered, with additional rescue doses if needed. Opioids that do not require complex hepatic metabolism, particularly those not heavily dependent on cytochrome enzymes (e.g., morphine, hydromorphone), are generally considered safer in this context [ 150 ]. In patients with asthma or chronic respiratory insufficiency, opioids are not contraindicated but should be prescribed with caution [ 140 , 143 ]. In cancer patients on buprenorphine OAT, several strategies may be considered for pain management. Buprenorphine may be continued and optimized, as no clear analgesic ceiling effect has been demonstrated at therapeutic doses (see Patients receiving prescribed opioid medications, OAT, or illicit opioids ). However, given the limited evidence-based guidance in this setting, treatment decisions should be individualized. Experts recommend avoiding the addition of full agonists for pain management. Instead, a switch to an alternative opioid may be considered, based on clinical judgment and multidisciplinary evaluation. In patients on methadone OAT: Methadone is typically administered once daily for OAT. For adequate analgesic coverage in cancer pain, the daily dose should be divided into two or three administrations. Additional rescue doses may be required, and background doses should be adjusted accordingly. Regular assessment of both efficacy and adverse effects is essential when initiating opioid therapy. During dose titration, the frequency of evaluation should be tailored to opioid’s pharmacokinetics [ 142 , 144 ]. Timing of efficacy and tolerance evaluation: o 60 min after oral morphine or oxycodone (immediate release). o 15 min after intravenous administration. o 30 min after subcutaneous administration. Timing of efficacy and tolerance evaluation: o 60 min after oral morphine or oxycodone (immediate release). o 15 min after intravenous administration. o 30 min after subcutaneous administration. 60 min after oral morphine or oxycodone (immediate release). 15 min after intravenous administration. 30 min after subcutaneous administration. If pain persists at the same intensity without adverse effects, the dose should be increased by 50–100%. If there is no response after two to three oral doses, switching to IV administration should be considered [ 142 ]. Any change in pain characteristics requires prompt comprehensive reassessment [ 142 , 144 ]. For neuropathic pain insufficiently controlled by opioids alone, adjuvant therapy with tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors (SNRIs), and/or anticonvulsants may be considered [ 140 , 143 ]. Management of common adverse effects: Constipation: Preventive treatment is required in all cases, based on lifestyle and dietary measures (adequate hydration, fiber-rich diet, physical activity) and laxatives, usually osmotic. Peripherally acting opioid antagonists, such as methylnaltrexone or naloxegol, may be used as second-line options if not contraindicated [ 140 , 143 ]. Transdermal fentanyl may cause less constipation than oral opioids [ 140 , 152 ]. Nausea: Often occurs during the first week of opioid initiation. Anti-emetic, such as haloperidol or metoclopramide, may be required [ 140 , 143 , 146 ]. Delirium: Onset should prompt consideration of an opioid switch [ 140 , 143 , 147 ], after ruling out other causes. Miosis: When not associated with somnolence or respiratory depression, indicates opioid exposure but not overdose [ 140 , 143 ]. Somnolence: May indicate overdose or, at treatment initiation, compensation from prior sleep debt. In a patient on a stable dose, consider other drugs that cause somnolence or alter opioid pharmacokinetics, new-onset hepatic or renal failure, hypercalcemia, or brain metastases [ 146 , 150 ]. Methylphenidate (a psychostimulant) may be considered to counter sedation, though switching opioids is generally preferable, as methylphenidate lacks marketing authorization for this indication in France [ 143 ]. Respiratory depression: A respiratory rate below ten breaths per minute requires dose reduction or discontinuation. Naloxone should be administered if the rate falls below 8 breaths per minute. Constipation: Preventive treatment is required in all cases, based on lifestyle and dietary measures (adequate hydration, fiber-rich diet, physical activity) and laxatives, usually osmotic. Peripherally acting opioid antagonists, such as methylnaltrexone or naloxegol, may be used as second-line options if not contraindicated [ 140 , 143 ]. Transdermal fentanyl may cause less constipation than oral opioids [ 140 , 152 ]. Nausea: Often occurs during the first week of opioid initiation. Anti-emetic, such as haloperidol or metoclopramide, may be required [ 140 , 143 , 146 ]. Delirium: Onset should prompt consideration of an opioid switch [ 140 , 143 , 147 ], after ruling out other causes. Miosis: When not associated with somnolence or respiratory depression, indicates opioid exposure but not overdose [ 140 , 143 ]. Somnolence: May indicate overdose or, at treatment initiation, compensation from prior sleep debt. In a patient on a stable dose, consider other drugs that cause somnolence or alter opioid pharmacokinetics, new-onset hepatic or renal failure, hypercalcemia, or brain metastases [ 146 , 150 ]. Methylphenidate (a psychostimulant) may be considered to counter sedation, though switching opioids is generally preferable, as methylphenidate lacks marketing authorization for this indication in France [ 143 ]. Respiratory depression: A respiratory rate below ten breaths per minute requires dose reduction or discontinuation. Naloxone should be administered if the rate falls below 8 breaths per minute. BTcP occurs in patients whose background pain is controlled with a strong opioid. It may be spontaneous and unpredictable, without identified triggers, or associated with unpredictable factors such as coughing, sneezing, gastrointestinal or bladder spasms, and headaches [ 153 ]. BTcP can also be predictable, occurring during voluntary actions (e.g., movement, eating, defecation, urination, swallowing) or triggered by care procedures (e.g., mobilization, hygiene care) or diagnostic/therapeutic interventions [ 153 ]. If background pain is inadequately controlled, the episodes should not be classified as BTcP, but rather a sign of insufficient treatment, disease progression, or therapeutic tolerance. Likewise, end-of-dose pain is not considered BTcP and should prompt reassessment of baseline therapy [ 153 ]. Management of BTcP: primarily relies on transmucosal fentanyl, except when the desired analgesic effect must last longer than 2 h, in which case morphine or oxycodone may be preferred [ 153 ]. Most BTcP episodes, regardless of their pathophysiological mechanism, respond to transmucosal fentanyl citrate. However, for neuropathic BTcP, baseline treatment with appropriate agents (e.g., antidepressants, antiepileptics) should be reassessed to reduce both frequency and intensity of episodes while avoiding unnecessary escalation of total opioid dosage. Adjuvant measures may include antiepileptics or antidepressants for neuropathic pain, or antispasmodics for visceral pain. Additionally, complications of long-term opioid therapy such as constipation or urinary retention should be identified and managed, as they may cause acute iatrogenic pain that is often overlooked [ 153 ]. Refractory pain is defined as pain that does not adequately respond to “standard” therapies although further analgesic options may still be available [ 148 ]. In such cases, management strategies may include opioid rotation (switching to another opioid), modification of the route of administration, such as intravenous administration for rapid titration or intrathecal administration in specific circumstances [ 148 ]. The choice of opioid should be based on the patient’s clinical condition, hepatic and renal function, and concomitant treatments [ 148 ]. Opioid rotation is recommended in the following situations [ 148 ]: Inadequate pain control despite appropriate opioid therapy at a sufficient dose (less than 30% relief or numeric rating scale ≥ 5/10). Development of tolerance. Significant adverse effects related to opioids. Medical considerations such as organ failure affecting pharmacokinetics or significant drug–drug interactions. Inadequate pain control despite appropriate opioid therapy at a sufficient dose (less than 30% relief or numeric rating scale ≥ 5/10). Development of tolerance. Significant adverse effects related to opioids. Medical considerations such as organ failure affecting pharmacokinetics or significant drug–drug interactions. When pain control is insufficient, a change in the route of administration, from oral or transdermal to intravenous, may be considered. If the patient is able to self-administer boluses, intravenous patient-controlled analgesia (PCA) can be implemented [ 140 ], either with the same opioid or as part of an opioid rotation strategy. No significant difference in efficacy has been demonstrated between these two approaches [ 154 ]. As a last resort, intravenous fentanyl or sufentanil (off-label use) may be considered, but only after consultation with a team experienced in their use [ 148 ]. Caution is required when using conversion ratios. Always use conservative (lower-bound) conversion ratios to ensure safety. When calculating the required dose of the new opioid, conversion tables [ 148 ] may be used but must always be interpreted critically in light of each clinical context. It is also recommended to prescribe rescue doses to allow therapeutic adjustment [ 148 ]. Opioid rotation to methadone may be considered in cases of refractory cancer pain, after assessment by a specialized palliative care or pain management team, and only as a second-line option after failure of other step III opioids [ 155 ]. Treatment initiation and titration must be performed in a hospital setting under the supervision of a specialized team, due to the risk of delayed overdose, which may occur up to 7 days after initiation and requires close monitoring [ 148 ]. Once the optimal dose has been reached, treatment continuation and prescription renewal can be managed by any physician [ 148 ]. Potential drug–drug interactions should be carefully assessed at initiation, during dose adjustments, and whenever a new treatment is introduced [ 148 ]. Good practice recommendations include [ 148 ]: Perform an ECG with QTc interval measurement and assessing serum potassium prior initiation; continue monitoring after stabilization. Establish a clear prescribing and monitoring protocol, documented in the medical record. Monitor adverse effects and implement appropriate management strategies if required. Remain vigilant for signs of opioid overdose (e.g., somnolence, respiratory rate ≤ 8 breaths/min). Ensure that an overdose management protocol is available in the medical record. Provide patient education about potential drug interaction with commonly used medications, in close collaboration with the primary care physician, pharmacist, and nursing team. Perform an ECG with QTc interval measurement and assessing serum potassium prior initiation; continue monitoring after stabilization. Establish a clear prescribing and monitoring protocol, documented in the medical record. Monitor adverse effects and implement appropriate management strategies if required. Remain vigilant for signs of opioid overdose (e.g., somnolence, respiratory rate ≤ 8 breaths/min). Ensure that an overdose management protocol is available in the medical record. Provide patient education about potential drug interaction with commonly used medications, in close collaboration with the primary care physician, pharmacist, and nursing team. Spinal analgesia, either intrathecal or epidural, combining opioids with local anesthetics, is recommended for palliative patients with refractory pain that remains uncontrolled despite the equivalent of approximately 300 mg/day of oral morphine, or in cases of severe adverse effects with systemic analgesics [ 140 , 148 ]. The number of cancer survivors continues to increase owing to advances in diagnosis and treatment. Although there is no universal definition of “cancer survivor” in oncology, the most widely accepted one (National Cancer Institute, National Comprehensive Cancer Network, National Coalition for Cancer Survivorship) defines a survivor as: “an individual is considered a cancer survivor from the time of diagnosis and throughout their life” [ 156 ]. Opioid prescription should be reserved for survivors with persistent pain that does not respond to standard treatments and that causes a significant physical and/or emotional burden [ 146 ]. Pain in cancer survivors is most often chronic in nature. When its intensity, impact, and underlying mechanisms warrant consideration of opioid therapy, management should follow principles applied to chronic non-cancer pain, favoring long-acting opioid formulations (see section " Appropriate Use of Opioid Analgesics in Chronic Non-Cancer Pain ", Appropriate use of opioid analgesics in chronic non-cancer pain). Preventive measures should be consistent with those recommended for long-term opioid use. Monitoring data from the United States indicate that short-acting opioids are associated with a higher risk of OUD compared with prolonged-release opioids [ 157 ]. In France, one study highlighted a high risk of OUD related to the use of transmucosal fentanyl for chronic non-cancer pain, whereas this risk is rare when used for cancer-related pain [ 158 ]. No specific tool has been validated to assess the risk of OUD in oncology patients. Some clinicians use scales developed for non-cancer pain, such as the Prescription Opioid Misuse Index Scale (POMI) scale [ 159 , 160 ]. Before initiating opioid therapy, particularly in patients likely to require long-term treatment, it is crucial to screen for major risk factors of OUD, including psychiatric and addictive comorbidities (e.g., tobacco, alcohol, and medication use) [ 146 , 150 ]. For patients with a substance use disorder, whether involving licit or illicit substances, multidisciplinary management is recommended. Pain relief should be ensured while minimizing OUD risk. Weekly dispensing of opioids, rather than monthly, may be proposed [ 150 ]. Patients with a history of physical dependence and/or OUD may be reluctant to start opioid treatment due to fear of relapse. A multidisciplinary approach, including addiction medicine support, is advisable [ 150 ]. In patients presenting with OUD, it is important to rule out insufficient pain relief, cognitive impairment, or poor patient understanding leading to irregular opioid intake before concluding misuse for recreational purposes. BTcP episodes should always be systematically assessed, identified, and treated [ 146 , 150 ]. OUD can also occur in patients receiving opioids for cancer-related pain, particularly when used for their anxiolytic effect. Such cases should prompt referral to a multidisciplinary team including specialists in addiction medicine and/or palliative care [ 146 , 150 ]. Figure 4 presents the algorithm for the management of a patient with chronic cancer-related pain for whom opioid analgesic treatment is considered. Fig. 4 Algorithm for the management of patients with chronic cancer-related pain, in whom treatment with an opioid analgesic is being considered Algorithm for the management of patients with chronic cancer-related pain, in whom treatment with an opioid analgesic is being considered

These national guidelines, developed under the auspices of the French National Authority for Health, provide comprehensive recommendations on the appropriate use of opioid analgesics in acute and chronic pain, both cancer-related and non-cancer-related. By considering opioids as a single pharmacological class, they emphasize prudent prescribing, prioritization of non-opioid and multimodal strategies, and systematic evaluation of the benefit–risk balance. Practical tools are provided to support prescribers in diverse clinical settings, from primary care to specialized units. These recommendations aim to promote safer and more consistent opioid prescribing practices, balancing effective pain relief with the prevention of dependence, opioid use disorder, and overdose. A second part of the guidelines, focused on the prevention and management of opioid use disorder and overdoses, will complement the present work.

These recommendations have several limitations. First, the underlying literature review covered publications up to December 2021 and therefore did not formally integrate all subsequent evidence or guideline updates. Nevertheless, several major recommendations and updated versions of previously cited guidelines were added to the manuscript when deemed clinically relevant. Second, despite prioritization of high-level evidence, some recommendations rely on expert consensus or lower levels of evidence, particularly in complex clinical situations such as perioperative management in patients receiving opioid agonist treatment.

Opioids exert analgesic effects by modulating nociceptive transmission at both the spinal and supraspinal levels, significantly improving pain management. However, due to their high potential for dependence and opioid use disorder (OUD) (see definitions in Appendix 1 in Supplementary Material), opioids are associated with increased healthcare utilization (e.g., consultations, hospitalizations) and serious health consequences, including potentially fatal overdoses, particularly among patients with comorbidities. The World Health Organization (WHO) has reported a rise in opioid-related harms in recent years, largely driven by increasing use in the management of chronic non-cancer pain [ 1 ]. From an epidemiological perspective, the European situation differs markedly from the North American opioid crisis, where opioids were implicated in two-thirds of the 71,568 overdose deaths reported in the United States in 2017 [ 2 ]. However, the Organization for Economic Co-operation and Development (OECD) has urged governments to take urgent action against the “opioid crisis”, which is spreading globally [ 3 ]. In its report covering 25 member countries between 2011 and 2016, the OECD reported a 20% overall increase in opioid-related deaths. While the steepest rises occurred in the United States and Canada, several European countries, including Sweden, Norway, Ireland, and England and Wales, have also reported significant increases in opioid-related mortality. These trends were largely driven by higher opioid prescribing for pain, whether appropriate or not [ 3 ]. In Europe, countries with robust drug monitoring systems, strict regulation of pharmaceutical advertising, and tightly controlled prescribing and dispensing practices appear less affected [ 4 ]. France belongs to this group, with one of the lowest opioid-related mortality rates among OECD countries: an estimated 300–400 fatal overdoses per year, primarily linked to methadone (40%) or heroin (20%), far ahead of analgesic opioids (12%) [ 2 , 5 , 6 ]. Nevertheless, cases of dependence and OUD have emerged, along with new patient profiles experiencing overdose who do not fit the “typical” drug user profile, such as opioid-naïve or occasional users, and patients who developed dependence following opioid analgesic treatment for non-cancer conditions [ 7 – 9 ]. Against this backdrop, the French National Agency for Medicines and Health Products Safety (Agence Nationale de Sécurité du Médicament et des produits de santé [ANSM]) published a national review of opioid analgesic consumption [ 4 ] and initiated comprehensive monitoring of analgesic use, notably through the French Addictovigilance Network [ 10 ]. For health authorities, the challenge is therefore to maximize the safety of opioid use while preserving access for patients with pain and/or dependence who genuinely need them, particularly in the context of an aging population where pain symptoms are increasingly prevalent. Pharmacologically, opioids are defined as compounds with affinity for endogenous opioid receptors, and most adverse effects are receptor-mediated and common to the entire drug class. Regardless of their pharmacological potency, the benefit–risk balance of opioid analgesics is primarily dose-dependent, with risks, including the development of OUD and overdose, shared across all opioids. In this context, the classification of opioid analgesics proposed by Lussier and Beaulieu [ 11 ] is preferable to the WHO’s three-step analgesic ladder (no opioid, weak opioids, strong opioids; steps 1–3), which was validated only for cancer-related pain and may provide false reassurance to prescribers and patients [ 12 ]. The WHO classification has been debated in chronic non-cancer pain and should not be applied in this context, while it remains a reference framework in cancer pain management. Accordingly, and with the aim of reducing overdose and dependence, these recommendations were developed using a comprehensive approach to opioid medications, encompassing both analgesics and opioid agonist treatment (OAT), in adults aged over 15 years. Principles for the prevention and management of physical dependence, OUD, and overdoses were integrated. To our knowledge, this represents the first set of cross-cutting national guidelines addressing these issues.

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