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Published on

15/7/2025

Nefopam

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

Nefopam: A non-opioid central analgesic for acute pain management

Nefopam is an active substance recognized for its central analgesic properties, distinguished from morphine by a chemical structure unrelated to that of traditionally known analgesics. Used primarily in the symptomatic treatment of acute painful conditions, particularly post-operative pain, nefopam constitutes a significant therapeutic option in multimodal pain management. This article explores in depth its characteristics, use, efficacy, safety profile, and current place in the 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 analogue of diphenhydramine (an H1 antihistamine), and its structure is also close to orphenadrine (an antimuscarinic). Contrary to popular belief, nefopam is not an opioid.

The precise mechanism of action of nefopam is not yet fully elucidated. However, in vitro studies on rat synaptosomes suggest an 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 also not fully understood.

It is important to note that nefopam has no anti-inflammatory or antipyretic action. In addition, it does not cause respiratory depression and does not slow intestinal transit, notable advantages compared to some other analgesics. However, nefopam has 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 post-operative shivering in clinical studies. It is classified as a level I analgesic by the World Health Organization (WHO) and is also among the anti-hyperalgesics in the Lussier and Beaulieu classification.

Indications and role in the therapeutic strategy

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

In the therapeutic strategy, NEFOPAM PANPHARMA 30 mg, film-coated tablet, is considered a therapeutic option in the multimodal management of acute pain. Multimodal analgesia is an approach that consists of combining different methods of combating acute pain, whether pharmacological or non-pharmacological, in order to optimize efficacy while minimizing the undesirable effects of each treatment. This approach is particularly suited to acute pain. Nefopam can be used as a first-line or second-line treatment in this context.

The target population for NEFOPAM PANPHARMA 30 mg, film-coated tablet, is restricted to patients treated for acute pain and is intended for adults and adolescents over 15 years of age. The drug is relevant for use in both hospitals and in the community.

The dosage of nefopam should be adapted to the intensity of the pain and the individual clinical response of each patient. It is generally recommended to use the minimum effective analgesic dosage, and the treatment should be of short duration, specifically targeting acute pain. The recommended initial dose is 1 to 2 tablets, which can be increased by one tablet as needed, up to a maximum dose of 6 tablets per day, divided into 3 doses. For further details on dosage, it is always recommended to refer to the Summary of Product Characteristics (SmPC).

Acute pain itself is defined as a "warning signal", a symptom of an underlying organic or pathophysiological condition. Its rapid and effective treatment, especially for post-operative and traumatic pain, has an immediate impact on patient comfort and reduces perioperative and peritraumatic morbidities. This treatment is also a crucial prevention factor against the development of chronic pain.

To assess pain intensity, tools such as the visual analog scale (VAS) and the simple numerical scale (SNS) are references. If self-assessment is not possible, a hetero-assessment is necessary. Therapeutic goals include a VAS score less than or equal to 30 mm or an SNS score less than or equal to 3, with specific sedation and analgesia scores.

Current acute pain management in emergency medicine utilizes a wide range of analgesic agents, including paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and nitrous oxide. Since the withdrawal of paracetamol/dextropropoxyphene combinations in 2010-2011, French recommendations have been revised, advocating paracetamol for mild to moderate pain, NSAIDs or weak opioids for moderate to severe pain, and strong opioids for severe pain. There is a growing recommendation 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 cases of traumatology, nefopam can be combined with morphine, MEOPA, or ketamine as part of multimodal analgesia. For acute neuropathic pain, low-dose nefopam can be used in combination with usual analgesics.

Among the clinically relevant comparators in the evaluation scope of oral nefopam are other presentations of reimbursable nefopam (injectable) and a multitude of other analgesics recommended for acute pain. This includes non-opioid analgesics (level I) such as paracetamol and NSAIDs, weak opioids (level II) such as tramadol or fixed combinations (codeine/paracetamol), inhaled anesthetic agents (MEOPA, methoxyflurane), and level III opioids (morphine, fentanyl, sufentanil, oxycodone), as well as IV anesthetics such as ketamine. Non-drug treatments (immobilization, thermotherapy, psychological approaches) are also essential in a multimodal approach.

Commercial forms and bioequivalence

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

It is in this context that NEFOPAM PANPHARMA 30 mg, film-coated tablet, was introduced. This is a generic drug of the specialty ACUPAN 30 mg, coated tablet, which was not included on the reimbursement lists. This is the first request for registration of a specialty based on nefopam administered orally.

The NEFOPAM PANPHARMA 30 mg film-coated tablet dossier is based on a bioequivalence study (study NFA-P2-746) comparing its pharmacokinetic profile to that of ACUPAN 30 mg coated tablet. This randomized, cross-over, single-blind study was conducted in 24 healthy volunteers and concluded the bioequivalence of the two nefopam tablet formulations. The pharmacokinetic parameters (AUC0-t and Cmax) were comparable, with ratios and confidence intervals within acceptable limits.

It is interesting to note that the pharmacokinetics of injectable nefopam administered orally has also been studied. The bioavailability of the parent molecule of nefopam is low (0.36 ± 0.13) after oral administration, probably due to a significant hepatic first-pass effect. The average 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 for oral use and why a dedicated oral form was necessary for more controlled and safe administration.

Clinical efficacy and current data

The evaluation of the clinical efficacy of nefopam in tablet form is mainly based on the efficacy data of injectable nefopam, in particular its morphine-sparing effect in the post-operative setting. However, the efficacy/adverse effects ratio of nefopam in oral form in acute pain is poorly established and needs to be clarified in relation to active comparators.

A 2017 network meta-analysis evaluated the efficacy of non-morphine analgesics (NMAs) alone or in combination in adults after major surgery receiving patient-controlled morphine analgesia. 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 asignificant morphine-sparing effect (reduced morphine consumption over 24 hours). Among NMAs used alone, nefopam showed a significant morphine-sparing effect (-10.3 mg over 24 hours versus 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 in this indication was not justified. A broader 2015 Cochrane review, compiling 39 reviews on single-dose oral analgesics for acute postoperative pain, also noted the absence of clinical data comparing oral nefopam to placebo. This highlights a 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 Société Française d'Anesthésie et de Réanimation (SFAR) and the Société Française d'Étude et de Traitement de la Douleur (SFETD). In their "Livre Blanc de la Douleur", nefopam is classified as an analgesic indicated for moderate pain. It also states that nefopam, even in its injectable form, can still be used orally, but with a dosage limited to 20 mg every 4 hours, due to its 36% bioavailability and metabolism to 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.

Tolerance profile and adverse effects

The tolerance profile of nefopam should be carefully considered due to its potential adverse effects, some of which may be frequent or significant.

The most frequently reported side effects are:

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

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

Vertigo
Tachycardia (accelerated heart rate)
Palpitations
Dry mouth
Urinary retention

Other atropinic effects, although never reported, may be observed. Cases of confusional states were added to the SmPC of nefopam-based specialties in 2017, following an analysis of adverse effects by the Pharmacovigilance Committee of the European Medicines Agency.

The Risk Summary of the NEFOPAM PANPHARMA Risk Management Plan (RMP) of July 2019 identifies several significant and potential risks:

Major risks identified :
- Patients with a history of seizure disorders
- Hypersensitivity to the active substance or excipients
- Hepatic insufficiency
- Renal insufficiency
Potential major 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, for example tachycardia
- Cardiovascular effects, for example hypotension
- Effects on the central nervous system (CNS), for example hallucination, confusion, lightheadedness
- Overdose in an elderly population, as initial dose
- Urinary retention
- Abuse and misuse (detailed below)
- Impairment of the ability to drive safely or operate machinery

Nefopam is contraindicated in the following cases:

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

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

Risk of abuse and drug dependence

An important and worrying 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 addictovigilance signal linked to nefopam dates back to 1987, with the publication of the first case of addiction. The first national survey of drug dependence was carried out in 1995.

An upsurge in misuse, particularly ofthe orally injectable form ("poured over a sugar cube"), led to an official joint pharmacovigilance and addictovigilance investigation in 2010-2011. Although the number of reports of abuse and dependence was considered low in relation to the high consumption of nefopam (which could be explained by under-reporting), analyses confirmed the risk of abuse and dependence, particularly in chronic pain sufferers.

Nefopam reimbursement data between 2006 and 2017 showed a continuous increase in the number of patients exposed. 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 (analgesia lasting more than 3 months), even though the marketing authorization does not allow it. This off-label use is frequent, with an estimated 70% of injectable nefopam prescriptions being used orally off-label, according to a 2018 report by the Académie Nationale de Médecine.

The patients concerned by this misuse were mainly women (63.3%) with a median age of 57 years. Prescriptions were often made by private physicians (72.6%), of which 86.1% were by general practitioners, and only 18.7% in a hospital setting. The most frequently co-prescribed analgesics were paracetamol, NSAIDs, and weak opioids.

The technical committee of the CEIP-A (Centres for Evaluation and Information on Pharmacodependence-Addictovigilance) pointed out in May 2019 that the misuse of the injectable specialty via the oral route was frequent, presenting a psychostimulant-type pharmacodependence profile and use in chronic pain. To address these problems, four proposals were issued:

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

It is essential to note that nefopam, being neither a morphine nor a morphine antagonist, its discontinuation in a physically dependent patient treated with nefopam should not be used as a substitute for opioids because it could lead to an opioid withdrawal syndrome. The risk of drug dependence does exist with nefopam, and cases of primary and secondary addiction have been observed.

Drug interactions

Nefopam drug interactions are important to consider due to its additive effects and potential impact on alertness. Caution should be exercised, and combinations verified before any prescription.

Unrecommended associations:

Alcohol: Alcohol increases the sedative effect of nefopam. It is therefore strongly discouraged to consume alcohol during treatment with nefopam.

Associations to consider: Nefopam may have additive effects with other molecules, particularly those that have depressant effects on the central nervous system (CNS). This alteration in alertness can make driving and operating machinery dangerous. Sedative medications to consider include:

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

In addition, the NEFOPAM PANPHARMA Risk Management Plan (RMP) identifies potential additive effects with:

Anticholinergics (e.g., solifenacin, diphenhydramine, dextromethorphan).
Sympathomimetics (e.g., ephedrine, methylphenidate).

These interactions highlight the need for healthcare professionals to conduct an in-depth analysis of prescriptions to avoid dangerous combinations and to inform patients of the risks associated with the concomitant intake of other substances.

Opinions of health authorities and reimbursement

The health authorities in France, and more particularly the Transparency Commission of the Haute Autorité de Santé (HAS), have issued a detailed opinion on NEFOPAM PANPHARMA 30 mg, film-coated tablet.

At its meeting on October 18, 2023, the Commission de la Transparence approved reimbursement in the indication "Symptomatic treatment of acute pain, particularly post-operative pain".

Regarding the Service Médical Rendu (SMR) [Medical Service Rendered], the Commission considered it to be MODERATE in the indication of the Marketing Authorization (AMM). This opinion takes into account the fact that rapid and effective treatment of acute pain has an immediate impact on patient comfort and can prevent the development of chronic pain. Nevertheless, it is noted that nefopam is a drug with a symptomatic purpose and that its efficacy/side effect ratio is poorly established and remains to be clarified compared to active comparators. NEFOPAM PANPHARMA 30 mg is therefore considered as a therapeutic option in the multimodal management of acute pain.

As for theAmélioration du Service Médical Rendu (ASMR), the Commission has concluded that NEFOPAM PANPHARMA 30 mg, film-coated tablet, offers no 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 superior clinical benefit to the injectable forms already available.

In terms of Public Health Interest (ISP), the Commission considered that this specialty 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 the usage data for injectable nefopam in 2022 (approximately 1.5 million "consumers"), taking into account that a large proportion of prescriptions for the injectable form were already being diverted for oral use.

The reimbursement rate proposed for registration on the list of specialties reimbursable to social security beneficiaries is 35%. The drug is also approved for use by communities.

The Commission reiterated the importance of its previous opinion, pointing out that nefopam has no marketing authorization for chronic pain. This clarification is essential to supervise the use of this new oral form and avoid transferring the 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 DCI sheet on 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 in the absence of relevant clinical studies. Similarly, exposure in children under 12 years of age is missing from the data provided.

For elderly subjects, particular caution is advised due to the anticholinergic effects of the product; treatment is even discouraged in the elderly according to the ANSM. The risk of initial dose overdose in this population is also an identified potential risk.

Patients with hepatic or renal insufficiency should also be treated with increased caution due to the risk of product accumulation and therefore an increased risk of adverse effects.

Finally, for all patients with cardiovascular disease, particular attention is required due to the tachycardic effect of nefopam. The treatment of myocardial infarction or cardiac pain is missing information in the nefopam usage data.

These considerations highlight 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 acute pain arsenal

NEFOPAM PANPHARMA 30 mg film-coated tablet, represents a new therapeutic option in the management of acute pain in France, marking the first registration of a nefopam-based specialty administered orally for reimbursement. Its arrival on the market aims to regulate the use of a substance whose injectable form was widely diverted orally, 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 shown 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 abuse and drug dependence, particularly if the drug is used for chronic pain, an indication for which it is not authorized. Strict adherence to 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 place in the medical service rendered and the lack of improvement compared to the injectable form highlight that it is above all a formalization of an already widespread mode of administration, with the aim of improving the safety of use and better controlling the prescription of this important analgesic. Continuous monitoring of its use and effects will be essential to confirm its beneficial role in the management of acute pain.