Nefopam

Nefopam is an active ingredient recognized for its central analgesic properties; it differs from morphine derivatives in that its chemical structure is unrelated to that of traditionally known analgesics.

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

Nefopam is an active ingredient recognized for its central analgesic properties; it differs from opioids in that its chemical structure is unrelated to that of traditionally known analgesics. Used primarily for the symptomatic treatment of acute pain, particularly postoperative pain, nefopam represents a significant therapeutic option in the multimodal management of pain. This article provides an in-depth examination of its characteristics, use, efficacy, safety profile, and current role 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 agent). 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 role in the treatment plan

Nefopam is specifically indicated for the symptomatic treatment of acute pain, particularly postoperative pain. It is important to note 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 treatment strategy, NEFOPAM PANPHARMA 30 mg film-coated tablets are considered a treatment 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 Analog Scale (VAS) and the Numerical Rating Scale (NRS) are standard references. 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 acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and nitrous oxide. Since the withdrawal of acetaminophen/dextropropoxyphene combinations in 2010–2011, French guidelines have been revised, recommending acetaminophen 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 standard analgesics. Clinically relevant comparators within the scope of evaluation for oral nefopam include other reimbursable (injectable) nefopam formulations and a wide range of other analgesics recommended for acute pain. These include non-opioid analgesics (step I) such as acetaminophen and NSAIDs, weak opioids (step II) such as tramadol or fixed-dose combinations (codeine/acetaminophen), 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 France as an injectable, marketed under the name Acupan. However, due to frequent misuse of the injectable form—specifically by taking it orally (such as by pouring the contents of 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 included in the reimbursement lists. This is the first application for registration of an orally administered nefopam-based product. 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 via urine (87% of the administered dose). These pharmacokinetic data partly explain why the injectable form was converted to oral administration and why a dedicated oral formulation was needed for more controlled and safer administration.

Clinical Efficacy and Current Data

The assessment of the clinical efficacy 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-to-adverse-effect ratio of oral nefopam in acute pain is poorly established and requires further clarification when compared to active comparators.

A 2017 network meta-analysis evaluated the efficacy of non-opioid analgesics (NANAs) used alone or in combination in adults who had undergone major surgery and were receiving patient-controlled analgesia (PCA). This analysis showed that the combination of two NMA, 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 nefopam, even in its injectable form, can be administered 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 evaluated due to its potential adverse reactions, some of which may be common or serious.

The most commonly reported adverse reactions are:

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

Common side effects (occurring in 1 to 10 out of every 100 people) 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, such as tachycardia

Cardiovascular effects, such as hypotension

Effects on the central nervous system (CNS), such as hallucinations, confusion, and dizziness

Overdose in the elderly population at the initial dose

Urinary retention

Abuse and misuse (detailed below)

Impaired ability to drive safely or operate machinery

Nefopam is contraindicated in the following cases:

Children under the age of 15
Seizures or a history of seizure disorders
Risk of angle-closure glaucoma
Risk of urinary retention associated with urethroprostatic disorders

Precautions for use are necessary in cases of hepatic or renal insufficiency (risk of accumulation and increased adverse effects), in patients with cardiovascular disease (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 on nefopam dates back to 1987, with the publication of the first case of addiction. The first national survey on drug dependence was conducted in 1995.

A resurgence in misuse, particularly the oral use of the injectable form ("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 steady increase in the number of patients exposed to the drug. 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 acetaminophen, NSAIDs, and weak opioids. The CEIP-A (Centers for Evaluation and Information on Drug Dependence-Addictovigilance) technical committee reiterated in May 2019 that the oral misuse of the injectable product 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 formulation (to prevent self-administration of nefopam via intravenous injection).
Limit the prescription duration of injectable nefopam to 28 days once the oral form is available on the market.
Continue to monitor nefopam.
Conduct further studies.

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

There is a risk of drug dependence with nefopam, and cases of primary and secondary addiction have been reported.

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.

Combinations Not Recommended:

Alcohol: Alcohol increases the sedative effect of nefopam. It is therefore strongly recommended that you avoid consuming alcohol while taking nefopam.

Interactions to consider: Nefopam may have additive effects when combined with other substances, particularly those that depress the central nervous system (CNS). This impaired alertness can make driving and operating machinery dangerous. Sedative medications to consider include:

Morphine derivatives (analgesics, cough suppressants, and substitution therapies).
Antipsychotics.
Sedative antidepressants (such as amitriptyline, doxepin, mianserin, mirtazapine, and trimipramine).
Barbiturates.
Benzodiazepines and other anxiolytics (such as meprobamate).
Hypnotics.
H1 antihistamines with sedative effects.
Centrally acting antihypertensives.
Baclofen.
Thalidomide.

Regarding 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, noting that nefopam does not have marketing authorization for chronic pain. This clarification is essential for regulating the use of this new oral form and preventing 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 note that information regarding these situations is missing from 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 conducting 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 for treating acute pain

NEFOPAM PANPHARMA 30 mg film-coated tablets represent a new therapeutic option for the management of acute pain in France, marking the first approval 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 use, 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 has not yet been 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 reports of misuse and a step toward better management of this active substance. Its limited role in medical practice and the lack of improvement compared to the injectable form underscore that it is primarily a formalization of an already widespread method of administration, with the objective of improving safety 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.