Nefopam

Nefopam is an active substance recognized for its central analgesic properties, distinguished from morphine derivatives by a chemical structure unrelated to that of traditionally known analgesics.

Nefopam: A Non-Opioid Central Analgesic for the Management of Acute Pain

Nefopam is an active substance recognized for its central analgesic properties, distinguished from opioids by a chemical structure unrelated to that of traditionally known analgesics. Used primarily in the symptomatic treatment of acute painful conditions, particularly postoperative pain, nefopam represents a significant therapeutic option in the multimodal management of pain. This article explores in depth its characteristics, use, efficacy, safety profile, and current place in therapeutic strategy.

What is Nefopam? Mechanism of Action and Properties

Nefopam is classified as a non-opioid central analgesic. Its chemical structure is unique; It is a benzoxazocine and a cyclic analog of diphenhydramine (an H1 antihistamine), and its structure is also similar to orphenadrine (an antimuscarinic). Contrary to popular belief, nefopam is not an opioid. The precise mechanism of action of nefopam is not yet fully understood. However, in vitro studies on rat synaptosomes suggest inhibition of catecholamine and serotonin reuptake. In vivo, in animals, nefopam has demonstrated antinociceptive properties and antihyperalgesic activity, although the mechanism of the latter is not fully understood. It is important to note that nefopam has no anti-inflammatory or antipyretic activity. Furthermore, it does not cause respiratory depression or slow intestinal transit, notable advantages over some other analgesics. However, nefopam does possess anticholinergic activity. Hemodynamically, a moderate and transient increase in heart rate and blood pressure has been observed. In addition, nefopam has shown an effect on postoperative shivering in clinical studies. It is classified as a level I analgesic by the World Health Organization (WHO) and is also listed among the antihyperalgesics in the Lussier and Beaulieu classification.

Indications and place in the therapeutic strategy

Nefopam is specifically indicated for the symptomatic treatment of acute painful conditions, particularly postoperative pain. It is imperative to emphasize that nefopam does not have a Marketing Authorization (MA) for chronic pain. This distinction is crucial for appropriate prescribing and to minimize the risks of misuse.

In the therapeutic strategy, NEFOPAM PANPHARMA 30 mg film-coated tablets are considered a therapeutic option in the multimodal management of acute pain. Multimodal analgesia is an approach that combines different methods of managing acute pain, both pharmacological and non-pharmacological, to optimize efficacy while minimizing the adverse effects of each treatment. This approach is particularly well-suited to acute pain. Nefopam can be used as a first- or second-line treatment in this context. The target population for NEFOPAM PANPHARMA 30 mg film-coated tablets is limited to patients being treated for acute pain and is intended for adults and adolescents over 15 years of age. The medication is suitable for use in both hospital and outpatient settings. The dosage of nefopam should be tailored to the intensity of the pain and the individual clinical response of each patient. It is generally recommended to use the minimum effective analgesic dose, and treatment should be short-term, specifically targeting acute pain. The recommended starting dose is 1 to 2 tablets, which may be increased by one tablet as needed, up to a maximum dose of 6 tablets per day, divided into 3 doses. For further dosage information, it is always recommended to refer to the Summary of Product Characteristics (SmPC). Acute pain itself is defined as a "warning sign," a symptom of an underlying organic or pathophysiological condition. Its rapid and effective treatment, particularly for postoperative and traumatic pain, has an immediate impact on patient comfort and reduces perioperative and peritraumatic morbidities. This treatment is also a crucial preventive factor against the development of chronic pain. To assess pain intensity, tools such as the Visual Analogue Scale (VAS) and the Numerical Rating Scale (NRS) are reference standards. If self-assessment is not possible, a hetero-assessment is necessary. Therapeutic goals include a VAS score of 30 mm or less, or an NRS score of 3 or less, with specific sedation and analgesia scores. Current management of acute pain in emergency medicine utilizes a wide range of analgesic agents, including paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and nitrous oxide. Since the withdrawal of paracetamol/dextropropoxyphene combinations in 2010-2011, French guidelines have been revised, recommending paracetamol for mild to moderate pain, NSAIDs or weak opioids for moderate to severe pain, and strong opioids for severe pain. It is increasingly recommended to limit the use of opioids to severe pain or when non-opioids are ineffective or contraindicated. Nefopam is one of these options. For example, in trauma cases, nefopam can be combined with morphine, nitrous oxide/oxygen (MEOPA), or ketamine as part of multimodal analgesia. For acute neuropathic pain, low-dose nefopam can be used in combination with usual analgesics. Clinically relevant comparators within the scope of evaluation for oral nefopam include other reimbursable (injectable) nefopam formulations and a multitude of other analgesics recommended for acute pain. These include non-opioid analgesics (step I) such as paracetamol and NSAIDs, weak opioids (step II) such as tramadol or fixed-dose combinations (codeine/paracetamol), inhaled anesthetic agents (MEOPA, methoxyflurane), and step III opioids (morphine, fentanyl, sufentanil, oxycodone), as well as IV anesthetics such as ketamine. Non-pharmacological treatments (immobilization, thermotherapy, psychological approaches) are also essential in a multimodal approach.

Commercial Forms and Bioequivalence

Historically, nefopam was primarily available in injectable form in France, marketed under the name Acupan. However, faced with frequent misuse of the injectable product orally (particularly by pouring the ampoule onto a sugar cube), and following recommendations from health authorities, the marketing of an oral form was encouraged.

It is in this context that NEFOPAM PANPHARMA 30 mg film-coated tablets were introduced. This is a generic version of the brand-name drug ACUPAN 30 mg coated tablets, which was not listed in the reimbursement lists. This is the first application for registration of a nefopam-based product administered orally. The dossier for NEFOPAM PANPHARMA 30 mg film-coated tablets is based on a bioequivalence study (study NFA-P2-746) comparing its pharmacokinetic profile to that of ACUPAN 30 mg coated tablets. This randomized, crossover, single-blind study was conducted in 24 healthy volunteers and concluded that the two nefopam tablet formulations were bioequivalent. The pharmacokinetic parameters (AUC0-t and Cmax) were comparable, with ratios and confidence intervals within acceptable limits. It is worth noting that the pharmacokinetics of injectable nefopam administered orally have also been studied. The bioavailability of the parent molecule nefopam is low (0.36 ± 0.13) after oral administration, likely due to significant first-pass hepatic metabolism. The mean plasma half-life of nefopam is approximately 4 hours after intravenous administration and 5.1 hours after oral administration. Nefopam is extensively biotransformed, producing three main metabolites, including desmethyl-nefopam, which is an active metabolite. The half-life of this metabolite is two to three times longer than that of the parent molecule (approximately 10–15 hours versus 3–8 hours for nefopam). Elimination is primarily urinary (87% of the administered dose). These pharmacokinetic data partly explain why the injectable form was diverted to oral administration and why a dedicated oral form was needed for more controlled and safer administration.

Clinical Efficacy and Current Data

The clinical efficacy assessment of nefopam in tablet form is based primarily on efficacy data for injectable nefopam, particularly its opioid-sparing effect in the postoperative setting. However, the efficacy/adverse effect ratio of oral nefopam in acute pain is poorly established and needs clarification compared to active comparators.

A 2017 network meta-analysis evaluated the efficacy of non-opioid analgesics (NANAs) alone or in combination in adults after major surgery receiving patient-controlled analgesia (PCA). This analysis showed that the combination of two NMAs, such as acetaminophen (paracetamol) and nefopam, or acetaminophen and NSAIDs, or tramadol and metamizole, was associated with a significant morphine-sparing effect (reduction in morphine consumption over 24 hours). Among NMAs used alone, nefopam showed a notable morphine-sparing effect (-10.3 mg over 24 hours compared to placebo). However, a 2009 Cochrane review highlighted the lack of studies evaluating the efficacy of oral nefopam compared to placebo in acute postoperative pain. Consequently, the authors of this review concluded that, in the absence of clear evidence of efficacy, the use of oral nefopam for this indication was not justified. A larger 2015 Cochrane review, compiling 39 reviews of single-dose oral analgesics for acute postoperative pain, also noted the lack of clinical data comparing oral nefopam to placebo. This highlights the need for further research to clearly establish the efficacy of oral nefopam compared to a placebo. Despite the lack of direct placebo-controlled studies for the oral form, nefopam is mentioned in the 2022 recommendations of the French Society of Anesthesia and Intensive Care (SFAR) and the French Society for the Study and Treatment of Pain (SFETD). In their "White Paper on Pain," nefopam is classified among the analgesics indicated for moderate pain. It is also specified that the use of nefopam, even in its injectable form, remains possible orally, but with a dosage limited to 20 mg every 4 hours due to its 36% bioavailability and its metabolism into desmethyl-nefopam, its active metabolite. It should be noted that the 2020 European Society for Emergency Medicine (EUSEM) guidelines on the management of acute pain in emergency situations do not mention nefopam. src="https://cdn.prod.website-files.com/61f1c5bbc327ec3679e7457c/6863060f400d5690eafa7f0b_freestocks-nss2eRzQwgw-unsplash.jpg" loading="lazy">

Safety Profile and Adverse Reactions

The safety profile of nefopam should be carefully considered due to its potential adverse reactions, some of which may be common or serious.

The most frequently reported adverse reactions are:

Very common (> 1/10):
- Drowsiness
- Nausea (with or without vomiting)
- Hyperhidrosis (excessive sweating)

Common side effects (between 1/100 and 1/10) include:

Dizziness
Tachycardia (rapid heartbeat)
Palpitations
Dry mouth
Urinary retention

Other atropine-like effects, although never reported, may occur. Cases of confusional states were added to the Summary of Product Characteristics (SmPC) for nefopam-based products in 2017, following an analysis of adverse effects by the Pharmacovigilance Committee of the European Medicines Agency. The Risk Summary of the Risk Management Plan (RMP) for NEFOPAM PANPHARMA from July 2019 identifies several important and potential risks: Important risks identified: Patients with a history of seizure disorders; Hypersensitivity to the active substance or excipients; Hepatic impairment; Renal impairment. Important potential risks: Concomitant administration with tricyclic antidepressants

Additive effect with anticholinergics (e.g., solifenacin, diphenhydramine, dextromethorphan)

Additive effect with sympathomimetics (e.g., ephedrine, methylphenidate)

Cardiac effects, e.g., tachycardia

Cardiovascular effects, e.g., hypotension

Central nervous system (CNS) effects, e.g., hallucinations, confusion, lightheadedness

Overdose in the elderly population, at the initial dose

Urinary retention

Abuse and misuse (detailed below)

Impaired ability to drive safely or operate machinery machines

Nefopam is contraindicated in the following cases:

Children under 15 years of age
Seizures or history of seizure disorders
Risk of angle-closure glaucoma
Risk of urinary retention related to urethroprostatic disorders

Precautions for use are necessary in cases of hepatic or renal insufficiency (risk of accumulation and increase of adverse effects), in patients suffering from cardiovascular diseases (due to the tachycardic effect), and in the elderly (due to anticholinergic effects). The benefit/risk ratio of nefopam treatment should be regularly reassessed.

Risk of Abuse and Drug Dependence

An important and concerning aspect of nefopam is the risk of drug dependence, abuse, and misuse. This risk has been documented for many years in France. The first French pharmacovigilance report related to nefopam dates back to 1987, with the publication of the first case of addiction. A first national drug dependence survey was conducted in 1995.

A resurgence of misuse, particularly the use of the injectable form orally ("poured onto a sugar cube"), led to a joint official pharmacovigilance and drug abuse monitoring survey in 2010-2011. Despite a relatively low number of reported cases of abuse and dependence compared to the significant consumption of nefopam (which could be explained by underreporting), analyses confirmed the risk of abuse and dependence, particularly among individuals suffering from chronic pain.

Reimbursement data for nefopam between 2006 and 2017 showed a continuous increase in the number of exposed patients. In 2017, nearly 1% of the French population had been exposed to nefopam. Alarmingly, one in two patients (49.2%) had been prescribed nefopam for chronic pain (pain relief lasting more than 3 months), even though this is not permitted under the marketing authorization. This misuse is frequent, with an estimated 70% of prescriptions for injectable nefopam being used orally off-label, according to a 2018 report by the French National Academy of Medicine. The patients affected by this misuse were predominantly women (63.3%) with a median age of 57. Prescriptions were often written by private practitioners (72.6%), including 86.1% by general practitioners, and only 18.7% in hospitals. The most frequently co-prescribed analgesics were paracetamol, NSAIDs, and weak opioids. The CEIP-A (Centers for Evaluation and Information on Drug Dependence-Addictovigilance) technical committee reiterated in May 2019 that the misuse of the injectable product by oral route was frequent, presenting a psychostimulant-type drug dependence profile and use in chronic pain. To address these problems, four proposals have been put forward:

Encourage the marketing of an oral form (to avoid IV self-administration of nefopam).
Limit the prescription duration of injectable nefopam to 28 days once the oral form is marketed.
Maintain monitoring of nefopam.
Conduct further studies.

It is essential to note that nefopam, being neither an opioid nor an opioid antagonist, should not be used as a substitute for opioids in a physically dependent patient treated with nefopam, as this could lead to opioid withdrawal syndrome.

The risk of drug dependence does exist with nefopam, and cases of primary and secondary addiction have been observed.

Drug Interactions

Drug interactions with nefopam are important to consider due to its additive effects and its potential impact on alertness. It is crucial to exercise caution and check for drug interactions before prescribing.

Not Recommended Combinations:

Alcohol: Alcohol increases the sedative effect of nefopam. It is therefore strongly advised against consuming alcohol during treatment with nefopam.

Interactions to consider: Nefopam can have additive effects with other molecules, particularly those that have central nervous system (CNS) depressant effects. This impaired alertness can make driving and operating machinery dangerous. Among the sedative medications to consider are:

Morphine derivatives (analgesics, antitussives, and substitution treatments).
Neuroleptics.
Sedative antidepressants (such as amitriptyline, doxepin, mianserin, mirtazapine, and trimipramine).
Barbiturates.
Benzodiazepines and other anxiolytics (such as meprobamate).
Hypnotics.
Sedative H1 antihistamines.
Centrally acting antihypertensives.
Baclofen.
Thalidomide.

Improvement in Medical Benefit (ASMR), the Commission concluded that NEFOPAM PANPHARMA 30 mg film-coated tablets did not provide any improvement (ASMR V) compared to ACUPAN 20 mg/2 mL injectable solution and its generics. This means that although it is a new oral dosage form, it does not offer a superior clinical benefit to the injectable forms already available. In terms of Public Health Interest (ISP), the Commission considered that this product is not likely to have an additional impact on public health. The number of patients likely to be treated with oral nefopam is estimated at approximately 1.1 million. This estimate is based on 2022 data on the use of injectable nefopam (approximately 1.5 million users), taking into account that a large proportion of prescriptions for the injectable form were already being diverted for oral use. The proposed reimbursement rate for inclusion on the list of reimbursable medications for social security beneficiaries is 35%. The drug is also approved for use in hospitals and other healthcare facilities. The Commission reiterated the importance of its previous opinion, recalling that nefopam does not have marketing authorization for chronic pain. This clarification is fundamental to regulating the use of this new oral form and preventing the transfer of misuse observed with the injectable form.

Special considerations: pregnancy, breastfeeding and specific populations

Although the sources provided do not detail the use of nefopam during pregnancy and breastfeeding, they mention that these situations represent missing information in the NEFOPAM PANPHARMA Risk Management Plan. However, the Vidal INN entry for injectable nefopam hydrochloride indicates a risk level II (precautions) for pregnancy and breastfeeding, suggesting that precautions should be taken. It is therefore essential to consult a healthcare professional to assess the benefit/risk ratio in these populations. Regarding children under 15 years of age, nefopam is contraindicated due to a lack of relevant clinical studies. Similarly, information on exposure in children under 12 years of age is missing from the data provided. For the elderly, particular caution is advised due to the product's anticholinergic effects, and treatment is even discouraged in the elderly according to the ANSM (French National Agency for Medicines and Health Products Safety). The risk of initial dose overdose in this population is also an identified potential risk. Patients with hepatic or renal impairment should also exercise increased caution due to the risk of product accumulation and therefore an increased risk of adverse effects. Finally, for all patients with cardiovascular disease, special attention is required due to the tachycardic effect of nefopam. The treatment of myocardial infarction or cardiac pain is a missing piece of information in the nefopam usage data.

These considerations underscore the importance of an individual assessment of the patient before prescribing nefopam, taking into account their medical history and any comorbidities.

Conclusion: A new tool in the arsenal of acute pain

NEFOPAM PANPHARMA 30 mg film-coated tablets represent a new therapeutic option in the management of acute pain in France, marking the first registration of an orally administered nefopam product for reimbursement. Its introduction to the market aims to regulate the use of a substance whose injectable form was widely diverted for oral administration, and to better control the risks associated with misuse and drug dependence. Although nefopam is a non-opioid central analgesic, with a distinct mechanism of action and advantages such as the absence of respiratory depression or slowing of intestinal transit, its specific efficacy profile for the oral form is not yet fully established compared to placebos. However, it has demonstrated a morphine-sparing effect in postoperative pain, making it a valuable addition to multimodal analgesia strategies. It is crucial for prescribers and patients to remain vigilant regarding potential adverse effects (drowsiness, nausea, tachycardia, anticholinergic effects) and the risks of misuse and dependence, particularly if the drug is used for chronic pain, an indication for which it is not approved. Strict adherence to the indications, dosage, and precautions for use, as well as regular reassessment of the benefit-risk ratio, are essential for the safe and effective use of nefopam. The introduction of NEFOPAM PANPHARMA in tablet form is a response to observations of misuse and a step towards better management of this active substance. Its moderate role in the medical service provided and the lack of improvement compared to the injectable form underline that it is primarily a formalization of an already widespread method of administration, with the objective of improving the safety of use and better regulating the prescription of this important analgesic. Continued monitoring of its use and effects will be essential to confirm its beneficial role in the management of acute pain.