Nefopam: A Comprehensive Pharmacological and Clinical Review

I. Introduction and Overview

A. Drug Identification

Nefopam is a centrally acting analgesic agent that is structurally and pharmacologically distinct from opioid analgesics and non-steroidal anti-inflammatory drugs (NSAIDs).[1] It is classified as a small molecule drug [2] and is marketed under various brand names, including Acupan.[1] For precise identification in scientific literature and databases, Nefopam is assigned the DrugBank ID DB12293 [1] and the Chemical Abstracts Service (CAS) Number 13669-70-0 for the base compound.[2] The hydrochloride salt, a common pharmaceutical form, is identified by CAS Number 23327-57-3.[2] These identifiers are crucial for unambiguous referencing in research and clinical practice.

B. Brief Summary of Therapeutic Use

Nefopam is primarily indicated for the relief of moderate to severe pain.[1] Its application is particularly prominent in acute pain settings, such as post-operative pain, dental pain, musculoskeletal pain, and certain types of cancer-related pain.[7] While its role in chronic pain management is less well-established, it is sometimes utilized when other analgesics are contraindicated or have proven ineffective.[1]

C. Historical Background and Development

Nefopam, a benzoxazocine derivative, was developed in the 1960s and initially introduced under the name Fenazoxine.[1] Its early therapeutic exploration was quite broad, with initial applications including the management of shivering, use as a muscle relaxant, and even as an antidepressant.[1] Over time, its utility as an analgesic agent became more distinctly recognized, leading to its current primary indication for pain relief.

The evolution of Nefopam's primary recognized use from these initial broader applications to a more focused role as an analgesic suggests that its complex pharmacological profile was not fully appreciated at the outset. It is plausible that its analgesic properties, while present, became more clinically apparent and valued through accumulated clinical experience or subsequent targeted research. This trajectory, where a drug's therapeutic scope is refined post-introduction, is not uncommon, particularly for compounds with multiple mechanisms of action. The early, more diverse applications such as for shivering, muscle relaxation, and antidepressant effects, provide early indications of its significant and varied impact on the central nervous system. These historical uses align with the more recently elucidated aspects of its pharmacology, such as its serotonin-norepinephrine-dopamine reuptake inhibiting (SNDRI) properties.[1] This understanding of its broader mechanistic footprint, hinted at by its early development history, now supports the exploration of its efficacy in other conditions, such as neuropathic pain, where such multimodal actions are considered beneficial.[4]

II. Chemical Properties and Synthesis

A. Physicochemical Characteristics

Nefopam is a derivative of benzoxazocine [1] and is structurally a cyclized analogue of other centrally acting compounds like orphenadrine and diphenhydramine.[1] The base form of Nefopam has a molecular formula of C17​H19​NO and a molecular weight of 253.34 g/mol.[2] Nefopam hydrochloride (C17​H19​NO⋅HCl), the commonly used salt form, has a molecular weight of 289.8 g/mol.[5]

The hydrochloride salt is typically a crystalline solid [6] or a white to beige powder.[15] Solubility data for Nefopam hydrochloride indicates it is soluble in dimethyl sulfoxide (DMSO) [5], slightly soluble in N,N-dimethylformamide (DMF), ethanol, and has a solubility of 0.5 mg/mL in phosphate-buffered saline (PBS) at pH 7.2.[6] It is also reported to be clearly soluble in water at 5 mg/mL.[15] Recommended storage conditions vary, with the base often stored at -20°C [3], while the hydrochloride salt may be stored at 2-8°C [15] or as a powder at -20°C for extended periods.[5]

Table 1: Key Chemical Identifiers and Properties of Nefopam and Nefopam Hydrochloride

Property	Nefopam (Base)	Nefopam Hydrochloride
IUPAC Name	5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine 2	3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine, monohydrochloride 6
CAS Number	13669-70-0 2	23327-57-3 2
Molecular Formula	C17​H19​NO 2	C17​H20​ClNO 5 or C17​H19​NO⋅HCl 6
Molecular Weight	253.34 g/mol 2	289.8 g/mol 5
SMILES	CN1CCOC(C2=CC=CC=C2C1)C3=CC=CC=C3 2	Cl.CN1CCOC(c2ccccc2)c3ccccc3C1 5
InChI	InChI=1S/C17H19NO/c1-18-11-12-19-17(14-7-3-2-4-8-14)16-10-6-5-9-15(16)13-18/h2-10,17H,11-13H2,1H3 2	InChI=1S/C17H19NO.ClH/c1-18-11-12-19-17(14-7-3-2-4-8-14)16-10-6-5-9-15(16)13-18;/h2-10,17H,11-13H2,1H3;1H 6
InChIKey	RGPDEAGGEXEMMM-UHFFFAOYSA-N 2	CNNVSINJDJNHQK-UHFFFAOYSA-N 6
Appearance	Not specified (typically solid)	Crystalline solid 6, white to beige powder 15
Key Solubilities (HCl)	N/A	DMSO: soluble 5; DMF, Ethanol: slightly soluble; PBS (pH 7.2): 0.5 mg/ml 6; H2​O: 5 mg/mL 15
Storage Conditions	-20°C 3	Powder: -20°C (3 yrs); In solvent: -80°C (1 yr) 5; 2-8°C (desiccated) 15

This consolidated chemical data is fundamental for researchers and chemists, providing unambiguous identification and essential physical properties for laboratory use and formulation development.

B. Chemical Structure

Nefopam's core structure is 5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine, classifying it within the benzoxazocine group of chemical compounds.[1] It is characterized as a tertiary amino compound.[2] This structural framework is key to its pharmacological activity and differentiates it from other analgesic classes.

C. Synthesis of Nefopam and Nefopam Hydrochloride

The synthesis of Nefopam hydrochloride typically commences with o-benzoylbenzoic acid (BB acid) as the primary starting material.[16] Patented methods describe multi-step processes aimed at achieving high yield and purity suitable for industrial production.

One detailed method (CN102363610A) involves the following sequence [16]:

1. Acyl Chloride Formation: o-benzoylbenzoic acid is reacted with an acylating agent, such as phosphorus trichloride, to produce an acyl chloride intermediate (acyl chlorides liquid A).
2. Amination: This acyl chloride is then reacted with N-Mono Methyl Ethanol Amine, typically in the presence of a base like triethylamine as a catalyst, to yield an aminated intermediate (amination liquid B).
3. Chlorination: The hydroxyl group in the aminated intermediate is subsequently converted to a chloride using a chlorinating agent (e.g., phosphorus trichloride), forming chlorated liquid C.
4. Reductive Hydrolysis: This crucial step involves the reduction of a carbonyl group within chlorated liquid C. The patent describes a specific, staged addition of reducing agents (e.g., potassium borohydride) and acetic acid to ensure a thorough reduction. This is followed by hydrolysis to yield an organic layer D containing the reduced intermediate. The complexity of this reduction step, involving careful control of reagent addition and reaction conditions, suggests that simpler reduction approaches may be less efficient or lead to undesirable side products. Optimizing this stage is likely critical for the overall yield and purity of the final product, potentially impacting manufacturing costs and consistency.
5. Ring-Closure Reaction: The intermediate in organic layer D undergoes cyclization, facilitated by an agent like hydrogen bromide, to form the characteristic benzoxazocine ring system of Nefopam (product E).
6. Neutralization and Salification: Finally, product E is neutralized (e.g., with sodium hydroxide) and then treated with concentrated hydrochloric acid to precipitate Nefopam hydrochloride. This product can be further purified by recrystallization, for instance, from an ethanolic solution.[16]

An alternative patented approach (CN102924320B) focuses on the synthesis of a key Nefopam intermediate, 2-benzoyl-N-(2-chloroethyl)-N-methyl-benzamide (Intermediate I).[18] This method involves acylating chlorination of o-benzoylbenzoic acid, reaction with N-Mono Methyl Ethanol Amine, subsequent chlorination with phosphorus trichloride at elevated temperature, and finally, purification of the intermediate by pH adjustment and precipitation.

The emphasis in these patents on achieving high yield, purity, and suitability for industrial production [16] indicates that these methods likely represent improvements over earlier, perhaps less efficient or scalable, synthetic routes. Such advancements are vital for ensuring a consistent and cost-effective supply of a widely used pharmaceutical agent.

III. Pharmacology

A. Mechanism of Action

Nefopam is a centrally-acting analgesic whose mechanism of action is distinct from that of opioids and NSAIDs.[1] While not fully elucidated, its analgesic effects are understood to arise from a combination of actions on multiple neurotransmitter systems and ion channels within the central nervous system.[1]

1. Neurotransmitter Reuptake Inhibition:

A primary mechanism involves the inhibition of reuptake of serotonin (5-HT), norepinephrine (noradrenaline, NA), and dopamine (DA).1 This action as a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) is thought to enhance descending pain inhibitory pathways, contributing significantly to its analgesic effect. This profile is shared by some antidepressant medications and may also underlie Nefopam's potential efficacy in neuropathic pain states.

2. Modulation of Ion Channels and Glutamatergic Transmission:

Nefopam also interacts with ion channels and the glutamatergic system:

• It blocks voltage-sensitive sodium channels, with a reported IC50​ of 27 µM in rodent studies.[1]
• It modulates voltage-gated calcium channels.[1]
• These ion channel effects, along with modulation of glutamatergic transmission, contribute to its antihyperalgesic activity.[1]
• Furthermore, Nefopam has been shown to inhibit N-methyl-D-aspartate (NMDA) receptor-mediated long-term potentiation, an effect likely stemming from the inhibition of calcium influx.[1]

The combination of SNDRI activity with sodium and calcium channel modulation, as well as NMDA receptor antagonism, provides Nefopam with a multi-modal analgesic profile. This is fundamentally different from the receptor agonism of opioids or the cyclooxygenase inhibition of NSAIDs. Such a diverse mechanism could explain its utility in pain conditions where opioids or NSAIDs are insufficient or contraindicated, and it likely underpins its observed opioid-sparing effects when used as an adjunctive analgesic.

Despite these identified actions, the assertion that its mechanism is "not fully understood" [10] persists in the literature. This suggests that the precise interplay between these various mechanisms, their relative contributions in different types of pain, or the potential involvement of other, as-yet-unidentified molecular targets might still be areas of active investigation. This pharmacological complexity could contribute to the observed variability in patient response and the relatively broad spectrum of side effects associated with Nefopam. Further research to delineate these aspects could lead to a more optimized and targeted use of the drug.

B. Pharmacokinetics

1. Absorption:

Nefopam is absorbed from the gastrointestinal tract following oral administration.7 Peak plasma concentrations (Cmax) are typically observed between 1 to 3 hours after an oral dose.7 However, the oral bioavailability of Nefopam in humans is reported to be low.1 One study indicated an oral bioavailability of approximately 36% for the parent drug, which could effectively increase to around 62% if the contribution of its active metabolite, N-desmethylnefopam, is considered.20 This low and potentially variable oral bioavailability can influence dosing consistency and the predictability of its clinical effect.

2. Distribution:

In terms of distribution, Nefopam is approximately 73% bound to plasma proteins.1 Therapeutic plasma concentrations have been reported to range from 49 to 183 nM.1 This moderate degree of protein binding suggests that a significant fraction of the drug remains unbound and pharmacologically active, though potential for displacement interactions with other highly protein-bound drugs exists.

3. Metabolism:

Nefopam undergoes extensive metabolism, primarily in the liver.1 The main metabolic pathway is N-demethylation, which results in the formation of N-desmethylnefopam, an active metabolite.1 Other identified metabolites include nefopam-N-oxide and its N-glucuronide conjugate.19 In humans, up to seven putative metabolites have been reported.19 The extensive hepatic metabolism implies a potential for drug-drug interactions with substances that induce or inhibit hepatic enzymes and necessitates caution when administering Nefopam to patients with hepatic impairment. The presence of an active metabolite with a longer half-life than the parent compound contributes to the overall duration of the drug's pharmacological effect.

4. Elimination:

Nefopam and its metabolites are primarily excreted via the kidneys into the urine; approximately 87% of an intravenously administered dose is recovered in the urine within 5 days in human subjects.1 A smaller fraction, around 8% of the dose, is eliminated in the feces.7 Less than 5% of an administered dose is excreted as unchanged Nefopam in the urine.7 The elimination half-life (t1/2​) of the parent Nefopam molecule is approximately 3 to 8 hours.1 Notably, its active metabolite, N-desmethylnefopam, possesses a longer elimination half-life, estimated to be between 10 to 15 hours.1 The predominant renal excretion route for metabolites underscores the need for dose adjustments in patients with renal impairment. The extended half-life of N-desmethylnefopam prolongs the overall pharmacological activity beyond what might be predicted from the parent drug's half-life alone.

Table 2: Summary of Nefopam Pharmacokinetic Parameters

Parameter	Value / Description	Source(s)
Oral Bioavailability	Low; ~36% (parent), ~62% (parent + active metabolite)	1
Tmax (Oral)	1-3 hours	7
Protein Binding (%)	~73%	1
Metabolism	Extensive hepatic; N-demethylation (to N-desmethylnefopam - active), N-oxidation, glucuronidation	1
Active Metabolite(s)	N-desmethylnefopam	1
Half-life (Parent Drug)	3-8 hours	1
Half-life (N-desmethylnefopam)	10-15 hours	1
Excretion	Primarily renal (metabolites, ~87% of IV dose); Fecal (~8%)	1
Unchanged in Urine (%)	<5%	7

The combination of low oral bioavailability and extensive hepatic metabolism, coupled with the formation of an active metabolite, strongly suggests a significant first-pass effect for Nefopam. This means a substantial portion of an orally administered dose is metabolized in the liver and/or gut wall before reaching systemic circulation. Such a characteristic can lead to considerable inter-individual variability in plasma concentrations and, consequently, in clinical response following oral administration. The availability of an injectable route of administration [9] circumvents this first-pass metabolism, likely leading to more predictable systemic exposure and therapeutic effect. Furthermore, the observed route-dependent differential effects, such as variations in analgesia, sedation, and drowsiness between equivalent intravenous and oral doses of Nefopam [19], imply that the metabolites, particularly N-desmethylnefopam (which would be present in higher concentrations after oral first-pass metabolism), may possess a somewhat different pharmacological profile or CNS penetration capability compared to the parent drug. These metabolite characteristics could contribute significantly to the observed differences in clinical effects depending on the route of administration.

IV. Clinical Applications

A. Approved Indications and Therapeutic Efficacy

1. Analgesia:

Nefopam is licensed for the relief of both acute and chronic pain.7 Its approved indications encompass a range of painful conditions, including post-operative pain, dental pain, musculoskeletal pain, acute traumatic pain, and cancer pain.7

• Post-operative pain: This is a primary and well-established indication for Nefopam.[1] A 2025 review identified Nefopam as an effective adjunctive analgesic in the postoperative setting, with benefits in overall pain management and a reduction in opioid consumption.[1] However, it is also noted that some evidence regarding its efficacy in this setting can be conflicting, and further supportive data, particularly for diverse pain populations and a more detailed understanding of adverse effects, may be required.[1]
• Chronic pain: In the context of chronic pain, Nefopam is typically considered when more common analgesic alternatives are contraindicated or have proven ineffective, or it may be used as an add-on therapy to an existing analgesic regimen.[1] It is noteworthy that prominent guidelines, such as those from the National Institute for Health and Care Excellence (NICE) for chronic pain, do not currently list Nefopam as a recommended treatment option. Similarly, the Scottish Intercollegiate Guidelines Network (SIGN) has concluded that there is insufficient evidence to make specific recommendations for its use in chronic pain management.[10] Despite these guideline positions, some smaller studies have suggested benefits, for example, in managing pain associated with rheumatoid arthritis.[10] Other studies have found its efficacy to be similar to that of other analgesics in osteoarthritic pain or cancer pain, although often accompanied by a higher incidence of side effects.[10]
• Neuropathic pain: The underlying mechanisms of Nefopam, particularly its SNDRI activity and ion channel modulation, suggest a potential role in the management of neuropathic pain.[4] Preclinical evidence from studies in mice with vincristine-induced neuropathy supports this potential application.[4]

2. Comparative Efficacy:

Nefopam's analgesic efficacy has been compared to various other agents:

• Versus Aspirin: In at least one clinical trial, Nefopam demonstrated significantly greater analgesic efficacy than aspirin, although this was associated with a higher incidence of side effects such as sweating, dizziness, and nausea, particularly at higher doses of Nefopam.[1]
• Versus Opioids (Morphine, Oxycodone): The relative potency of Nefopam to morphine has been estimated such that 20 mg of Nefopam HCl provides an analgesic effect approximately equivalent to 12 mg of morphine.[1] It is considered to have comparable analgesic efficacy to morphine or oxycodone but tends to produce fewer opioid-associated side effects, notably lacking respiratory depression, and possesses a much lower potential for abuse.[1] A key benefit is its ability to reduce overall opioid consumption when used as an adjunctive agent.[1] Studies involving patient-controlled analgesia (PCA) have shown that combining Nefopam with fentanyl can effectively reduce the total fentanyl dose required.[24]
• Versus NSAIDs: Nefopam appears to be no more potent than NSAIDs.[10] Comparative studies against NSAIDs like flurbiprofen or diclofenac have generally found similar levels of analgesic effectiveness, but with a tendency for more side effects with Nefopam.[10] A meta-analysis by Evans et al. concluded that Nefopam was as effective as NSAIDs in controlling postoperative pain but was associated with an increased risk of nausea, vomiting, and sweating.[17] Importantly, unlike NSAIDs, Nefopam does not affect platelet function and lacks anti-inflammatory effects.[17]
• Versus Paracetamol: The combination of Nefopam and paracetamol has been shown to provide effective pain relief, with evidence suggesting a potential for synergistic interaction.[17] A preclinical study in a murine model of postoperative pain demonstrated a synergistic antinociceptive effect for mechanical hypersensitivity when low oral doses of Nefopam and paracetamol were co-administered.[25]

These comparisons position Nefopam as a unique non-opioid analgesic. Its primary strengths lie in acute and postoperative pain management, where its opioid-sparing properties are particularly valuable. However, its side effect profile must be carefully weighed against other non-opioid alternatives.

B. Other Established Medical Uses

Beyond its primary role as an analgesic, Nefopam has other established medical applications, leveraging its diverse central nervous system effects:

• Prevention of Shivering: Nefopam is effective in preventing perioperative shivering, which can occur during surgery or in the immediate recovery period following anesthesia.[1]
• Treatment of Severe Hiccups: It is also utilized for the management of severe, intractable hiccups.[1]

C. Off-Label and Investigational Uses

Nefopam continues to be investigated for various applications, some of which build upon its known mechanisms or historical uses. It is important to clarify that initial information suggesting Nefopam was under investigation for the "prevention of Cholecystitis" and "prevention of Kidney Transplantation" [2] appears to be a misinterpretation. The available clinical research focuses on pain management in the context of these conditions, rather than prevention of the conditions themselves.

1. Post-Cholecystectomy Pain Management:

Nefopam has been studied for its role in managing postoperative pain following laparoscopic cholecystectomy (LC).22

• A meta-analysis of randomized controlled trials (RCTs) found that while Nefopam did not demonstrate a statistically significant effect on reducing postoperative pain severity at 30 minutes or 60 minutes compared to placebo after LC, it did lead to a reduction in postoperative opioid consumption, an increase in the time to the first request for rescue analgesia, and a decrease in the number of patients requiring supplementary analgesics. Importantly, Nefopam did not increase the incidence of postoperative nausea and vomiting in this setting.[22]
• One study investigating the median effective dose (ED50) of Nefopam for post-LC pain determined it to be 62.1 mg. This is notably higher than some previously recommended or standard doses (e.g., 20 mg IV). The study also highlighted pain upon injection as a potential issue, particularly at these higher doses.[28]
• Another clinical trial found that patient-controlled analgesia (PCA) using Nefopam alone was non-inferior to a combination of Nefopam and fentanyl in PCA for managing pain after LC.[29] The consistent observation of opioid-sparing effects across various postoperative settings, including general surgery [1], laparoscopic cholecystectomy [22], and kidney transplantation [30], suggests that this is a robust and clinically relevant characteristic of Nefopam. This benefit is likely attributable to its non-opioid, multi-modal mechanism of action, which allows it to contribute to analgesia via pathways distinct from opioid receptors, thereby reducing the reliance on opioid analgesics and their associated side effects.

2. Prevention of Post-Anaesthetic Shivering (Clinical Trial Evidence):

While already used off-label for this purpose, Nefopam is also formally under investigation for the prevention of post-anaesthetic shivering.2

• An ongoing clinical trial (NCT06627816) is specifically designed to evaluate the efficacy of intravenous Nefopam (at a dose of 0.15 mg/kg) compared to dexmedetomidine and meperidine in preventing shivering after spinal anesthesia. The primary outcome measure is the incidence of shivering (defined as a shivering score ≥ 3 on a validated scale) over a 120-minute observation period.[31]
• Previous research cited in support of this trial suggests that Nefopam 0.15 mg/kg has comparable efficacy to dexmedetomidine 0.5 µg/kg, and that Nefopam 20 mg is as effective as meperidine 50 mg for shivering prevention, with the potential advantage of causing less sedation and hypotension than dexmedetomidine.[31] Other ongoing trials also list shivering prevention as an effect of Nefopam.[32]

3. Pain Management in Kidney Transplant Recipients (Clinical Trial Evidence):

Nefopam has been investigated for postoperative pain management in patients undergoing kidney transplantation (KT).2

• A retrospective study involving living-donor KT recipients demonstrated that the addition of intraoperative paracetamol and Nefopam infusions to a standard transversus abdominis plane (TAP) block resulted in improved postoperative pain control. This was evidenced by lower Visual Analog Scale (VAS) pain scores at 1 and 6 hours post-surgery, both at rest and during coughing, as well as reduced consumption of opioids via PCA devices, compared to patients who received a TAP block alone.[30]
• Nefopam is considered a suitable analgesic option for KT recipients due to its non-opioid and non-steroidal properties, and its relatively favorable safety profile in the context of renal dysfunction.[33]
• Another clinical trial (KCT0007351) compared Nefopam with propacetamol for managing visceral pain in living kidney donors, with findings suggesting that Nefopam provided a greater analgesic effect.[34]

4. Potential in Parkinson's Disease:

There is some suggestion that Nefopam may have efficacy in treating Parkinson's disease, potentially acting in a manner similar to bupropion and methylphenidate.1 This theoretical application is likely linked to its dopamine reuptake inhibiting properties, a core component of its SNDRI mechanism. However, clinical evidence supporting this use is minimal within the provided information.

The higher ED50 of 62.1 mg reported in the post-laparoscopic cholecystectomy study [28], when contrasted with the more commonly recommended intravenous doses (e.g., 20 mg), along with the noted issue of injection pain at such higher doses, suggests that optimizing Nefopam's therapeutic window for specific surgical procedures or pain intensities might be challenging. It implies that a standardized "one-size-fits-all" dosing approach may not be optimal, and that procedure-specific or even patient-specific titration might be necessary, carefully balanced against local and systemic tolerability.

Table 3: Summary of Key Clinical Trials for Investigational Uses of Nefopam

Indication	Trial ID / Study Ref.	Drug(s) & Comparator(s)	Key Outcome(s)	Summary of Findings	Source(s)
Post-Cholecystectomy Pain	Meta-analysis	Nefopam vs. Placebo	Pain severity, opioid consumption, time to rescue analgesia, adverse events	No significant ↓ in pain severity; ↓ opioid consumption, ↓ need for rescue analgesia, ↑ time to rescue; No ↑ PONV.	22
	Choi et al. 28	Nefopam (various doses, up-and-down method)	ED50 for pain relief (NPS <3)	ED50 = 62.1 mg; injection pain reported.	28
	29	Nefopam PCA vs. Nefopam-Fentanyl PCA	Postoperative pain (NRS), adverse effects	Nefopam alone PCA non-inferior to combination PCA for analgesia, lower adverse effects.	29
Post-Anaesthetic Shivering Prevention	NCT06627816	Nefopam (0.15 mg/kg IV) vs. Dexmedetomidine vs. Meperidine	Incidence of shivering (score ≥ 3) over 120 min	Ongoing trial. Previous data suggests comparable efficacy to comparators with potentially better side effect profile than dexmedetomidine.	31
Kidney Transplant Recipient Pain	Retrospective Study	Nefopam + Paracetamol + TAP block vs. TAP block alone	VAS pain scores, PCA opioid consumption	↓ VAS pain scores at 1h & 6h (rest & cough), ↓ PCA opioid consumption with Nefopam + Paracetamol.	30
	KCT0007351	Nefopam vs. Propacetamol (in living kidney donors)	Analgesic effect for visceral pain, opioid requirement	Nefopam provided greater analgesic effect for visceral pain and enhanced effects of blocks reducing opioid requirement.	34

V. Dosage and Administration

A. Recommended Dosages

The recommended dosage of Nefopam varies depending on the route of administration and patient factors:

• Oral Administration (Adults):
• The typical starting dose ranges from 30 mg to 60 mg, administered three times a day.[10]
• This dose can be increased based on clinical response, up to a maximum of 90 mg three times a day.[10]
• Some sources recommend a starting dosage of two 30 mg tablets (total 60 mg) three times daily, with a general range of one to three 30 mg tablets three times daily.[7]
• Injectable Administration (Adults):
• Intramuscular (IM): The usual dose is 20 mg administered every 6 hours as needed, with a maximum daily dose of 120 mg.[9]
• Intravenous (IV) Infusion (slow): A dose of 20 mg can be administered via slow intravenous infusion every 4 hours as needed, also with a maximum daily dose of 120 mg.[9] Single intravenous doses of 20 mg should be administered slowly, typically over a period of 15 to 20 minutes, to minimize potential acute side effects.[11]

B. Administration Guidelines

• Oral Administration: Nefopam tablets can be taken with or without food. They should be swallowed whole with a drink of water.[9]
• Injectable Administration: For intravenous use, Nefopam should be diluted with commonly used intravenous fluids, such as sodium chloride solution or isotonic glucose solution. It is important not to mix Nefopam with other injectable medications in the same syringe to avoid potential incompatibilities.[9] Following injection, it is recommended that the patient rests for 15 to 20 minutes to allow for monitoring for acute adverse effects such as dizziness, nausea, or sweating.[9]
• Duration of Use: The duration of Nefopam therapy depends on the indication. For acute pain, such as that following an operation, treatment may only be required for a short period (e.g., a few days). For chronic pain conditions, such as cancer pain, longer-term use may be necessary. It is generally advisable to use the lowest effective dose for the shortest duration necessary to control symptoms. If Nefopam has been taken for an extended period, the dose should be tapered gradually upon discontinuation to prevent potential withdrawal symptoms.[36]

C. Special Populations

Adjustments to dosage and administration are necessary for certain patient populations:

• Elderly (>65 years): Elderly patients generally require a reduced dosage of Nefopam. This is due to slower drug metabolism and an increased susceptibility to central nervous system (CNS) side effects, such as confusion and hallucinations, which have been reported in this age group.[1] A recommended starting oral dose for elderly patients is 30 mg three times daily.[7] The consistent emphasis across multiple sources on dose reduction and increased caution in the elderly signifies that Nefopam likely has a narrower therapeutic index in this demographic. This is probably due to a combination of age-related changes in pharmacokinetics (e.g., reduced metabolic capacity leading to slower clearance) and pharmacodynamics (e.g., increased sensitivity of the aging brain to the drug's CNS effects).
• Renal Impairment: Patients with end-stage renal disease (ESRD) may experience increased peak serum concentrations of Nefopam, and therefore, a dose reduction is recommended.[7] Both hepatic and renal insufficiency can interfere with the metabolism and excretion of Nefopam.[7] As with the elderly, this caution reflects the potential for drug accumulation and exaggerated side effects if standard doses are used in patients with compromised renal function.
• Hepatic Impairment: Caution is advised when administering Nefopam to patients with hepatic insufficiency, as this condition may interfere with its metabolism.[7]
• Pediatric Population: The safety and efficacy of Nefopam have not been formally evaluated in children under 12 years of age for oral administration, or under 15 years of age for the injectable form. Consequently, no specific dosage recommendations can be provided for these age groups.[7] The European Medicines Agency (EMA) has granted a waiver for a paediatric investigation plan (PIP) for a combination product of Nefopam and paracetamol.[39] The general lack of pediatric data and the specific EMA waiver for the combination product suggest that establishing safe and effective pediatric use for Nefopam is challenging. This may be due to a variety of factors, including ethical considerations inherent in conducting clinical trials in children for analgesics, known developmental differences in drug metabolism and response, or potentially a lack of commercial incentive for pursuing pediatric indications. This situation represents an unmet need if effective non-opioid analgesic alternatives are being sought for pediatric patients.

VI. Safety Profile

A. Adverse Effects

Nefopam is associated with a range of adverse effects, primarily affecting the central nervous, gastrointestinal, and cardiovascular systems. The frequency of many side effects is often cited as "not known" due to limitations in reporting data, but some are widely recognized as common.

• Common Adverse Effects:
• Gastrointestinal: Nausea is very common.[1] Dry mouth is also frequently reported.[1] Abdominal pain can occur.[10]
• Nervous System: Light-headedness and dizziness are common.[1]
• Autonomic: Sweating is a common side effect.[1]
• Renal/Urinary: Urinary retention can occur.[1]
• Psychiatric: Nervousness is reported.[1]
• Vascular: Hypotension can be a common issue.[10]
• Less Common / Other Reported Adverse Effects:
• Gastrointestinal: Vomiting, diarrhoea.[1]
• Nervous System: Drowsiness, insomnia, headache, confusion (particularly in the elderly), tremor, paraesthesia, syncope, convulsions (seizures), coma.[1]
• Psychiatric: Hallucinations (especially in the elderly), agitation.[1]
• Cardiovascular: Tachycardia, palpitations, aggravation of angina.[1]
• Eye Disorders: Blurred vision.[1]
• Skin and Subcutaneous Tissue Disorders: Angioedema, allergic reactions (e.g., rash, hives).[7]
• Renal/Urinary: Rarely, a temporary and harmless pink discoloration of the urine has been observed.[1]
• Immune System Disorders: Allergic reaction, anaphylactic reactions.[7]
• Long-term Use: Prolonged use of Nefopam may lead to symptoms such as tiredness, low mood, anxiety, and restlessness. Discontinuation after long-term use can result in withdrawal symptoms.[37]
• Safety Concerns: There have been reports of Nefopam abuse, associated with psychostimulant effects including tremor, involuntary movements, aggression, violence, agitation, facial dysaesthesia, myoclonus, sweating, dry mouth, and depression.[23]

The diverse safety profile of Nefopam, particularly the prominent CNS effects (such as dizziness, drowsiness, confusion, and hallucinations), anticholinergic effects (like dry mouth and urinary retention), and sympathomimetic effects (such as tachycardia), strongly suggests a complex interaction with multiple neurotransmitter systems. This multifaceted pharmacological activity, while contributing to its analgesic properties, concurrently broadens the spectrum of potential adverse events.

Table 4: Common and Less Common Adverse Effects of Nefopam by System Organ Class

System Organ Class	Adverse Effect	Reported Frequency (Often "Not Known")	Source(s)
Immune system disorders	Allergic reaction, anaphylactic reactions, angioedema	Not known	7
Psychiatric disorders	Nervousness, insomnia, confusional state, hallucination (esp. elderly), agitation	Not known (Nervousness: Common)	1
Nervous system disorders	Light-headedness, dizziness, drowsiness, headache, tremor, paraesthesia, syncope, convulsions, coma	Not known (Light-headedness, Dizziness: Common)	1
Eye disorders	Blurred vision	Not known	1
Cardiac disorders	Palpitations, tachycardia, aggravation of angina	Not known (Tachycardia: can be common)	1
Vascular disorders	Hypotension	Not known (can be common)	7
Gastrointestinal disorders	Nausea, vomiting, dry mouth, abdominal pain, diarrhoea	Not known (Nausea, Dry Mouth: Common)	1
Skin and subcutaneous tissue disorders	Sweating, rash, hives	Not known (Sweating: Common)	1
Renal and urinary disorders	Urinary retention, pink discoloration of urine (harmless)	Not known (Urinary retention: can be common)	1

B. Contraindications

Nefopam is contraindicated in the following situations:

• Known hypersensitivity to Nefopam or any of its excipients.[7]
• Patients with a history of convulsive disorders (seizures).[7]
• Concomitant use with Monoamine Oxidase Inhibitors (MAOIs) or within 14 days of discontinuing MAOI therapy.[1]
• Children under 12 years of age (for oral formulations) or under 15 years of age (for injectable formulations).[9]
• Nefopam should not be used for the treatment of pain associated with myocardial infarction, as there is no clinical experience in this specific indication.[7]

C. Warnings and Precautions

Specific warnings and precautions should be observed when prescribing or administering Nefopam:

• Elderly Patients: Use with caution and at reduced dosages due to increased susceptibility to CNS side effects, particularly confusion and hallucinations.[1]
• Renal and Hepatic Insufficiency: Nefopam metabolism and excretion may be impaired in patients with renal or hepatic insufficiency. Use with caution, and dose reduction may be necessary.[7]
• Urinary Retention: Exercise caution in patients with a history of, or at risk of, urinary retention (e.g., due to prostatic disorders).[1]
• Angle-Closure Glaucoma: Use with caution in patients with angle-closure glaucoma.[7]
• Cardiovascular Disease: Nefopam may increase heart rate; therefore, caution is advised in patients with underlying cardiovascular conditions.[9] As noted, it should be avoided in the context of myocardial infarction.[7]
• Drug Dependence and Abuse: Cases of Nefopam dependence and abuse have been reported. It should be used with caution, particularly in individuals with a history of substance abuse.[7] The warnings concerning potential for abuse and dependence, despite Nefopam being a non-opioid analgesic, are noteworthy. These concerns might be linked to its dopaminergic and possibly serotonergic activity, components of its SNDRI mechanism, which could impart some centrally rewarding or psychostimulant properties, as suggested by reports of such effects.[1] While likely much less pronounced than with classical stimulants or opioids, this aspect warrants careful patient selection and monitoring.
• Driving and Operating Machinery: Nefopam can cause drowsiness and dizziness, which may impair the ability to drive or operate heavy machinery. Patients should be advised accordingly.[9]
• Interference with Screening Tests: Nefopam may interfere with certain laboratory screening tests, potentially causing false positive results for benzodiazepines and opioids.[7]

D. Drug Interactions

Nefopam has the potential for clinically significant drug interactions:

• Monoamine Oxidase Inhibitors (MAOIs): Co-administration is contraindicated due to the risk of severe adverse reactions, including hypertensive crises and serotonin syndrome.[1]
• Tricyclic Antidepressants (TCAs): Use with caution. There is an additive risk of anticholinergic side effects, and the potential for serotonin syndrome is increased.[1]
• Anticholinergic Agents: Concomitant use can lead to additive anticholinergic effects, such as dry mouth, blurred vision, constipation, and urinary retention.[1]
• Sympathomimetic Agents: Additive sympathomimetic effects, such as tachycardia and hypertension, may occur.[1]
• Serotonergic Drugs (e.g., SSRIs): Increased risk of serotonin toxicity, particularly in cases of overdose or with high doses of multiple serotonergic agents.[10]
• Sedative Medications and Alcohol: Nefopam can potentiate the CNS depressant effects of sedative medications and alcohol.[9]

Table 5: Significant Drug Interactions with Nefopam

Interacting Drug/Class	Potential Effect	Clinical Recommendation/Management	Severity	Source(s)
Monoamine Oxidase Inhibitors (MAOIs)	Hypertensive crises, serotonin syndrome	Contraindicated	Major	1
Tricyclic Antidepressants (TCAs)	Additive anticholinergic effects, potential serotonin syndrome	Use with caution; monitor for adverse effects	Moderate	1
Other Anticholinergic Agents	Increased anticholinergic burden (dry mouth, urinary retention, blurred vision)	Use with caution; monitor for anticholinergic side effects	Moderate	1
Sympathomimetic Agents	Additive sympathomimetic effects (tachycardia, hypertension)	Use with caution; monitor cardiovascular parameters	Moderate	1
Other Serotonergic Drugs (e.g., SSRIs)	Potential for serotonin syndrome	Use with caution, especially at high doses or in combination; monitor for symptoms	Moderate	10
Sedative Medications / Alcohol	Increased CNS depression	Avoid or use with extreme caution; advise patient of increased sedation risk	Moderate	9

E. Overdose

Overdose with Nefopam can be serious and has been associated with fatalities.[1]

• Manifestations: The clinical presentation of Nefopam overdose primarily involves neurological and cardiovascular symptoms. Neurological effects include convulsions, hallucinations, agitation, and potentially coma. Cardiovascular manifestations include tachycardia and a hyperdynamic circulatory state.[1] Serotonin toxicity can also occur, particularly if other serotonergic drugs have been co-ingested.[10]
• Management: Treatment of Nefopam overdose is primarily supportive. Activated charcoal may be administered to limit further absorption if ingestion was recent. Cardiovascular complications, such as tachycardia, may be managed with beta-adrenergic blockers. Neurological symptoms like convulsions and hallucinations should be controlled, for example, with intravenously or rectally administered diazepam.[1]

F. Use in Pregnancy and Lactation

• Pregnancy: The use of Nefopam during pregnancy is generally not recommended due to limited research on its safety in this population.[9]
• Lactation: Nefopam is not approved by the U.S. Food and Drug Administration (FDA).[2] Small amounts of Nefopam are excreted into breastmilk. However, one study indicated that Nefopam does not appear to adversely affect milk supply or the neurobehavioral scores of breastfed neonates.[2] Some sources consider breastfeeding acceptable during maternal use of Nefopam, although others recommend discontinuing its use after 48 hours postpartum.[2]

VII. Regulatory Status

The regulatory status of Nefopam varies significantly across different regions and countries.

A. United States (FDA)

In the United States, Nefopam is not approved for marketing by the Food and Drug Administration (FDA).[2] Consequently, its safety and efficacy have not been formally established according to FDA standards.[46] The FDA has issued public notifications regarding the presence of Nefopam as an undeclared, hidden ingredient in some unapproved products marketed as "dietary supplements" for joint and muscle pain relief.[46]

B. Europe (EMA and individual countries)

Nefopam is available as a prescription medicine in several European countries. These include the United Kingdom (where it is classified as a Prescription Only Medicine - POM), France, Belgium, and Germany.1

Historically in France, only the parenteral (injectable) formulation of Nefopam was officially authorized. However, the oral administration of this intravenous formulation was reportedly a common off-label practice.20 An oral tablet formulation (typically 30 mg) is available in other European countries like Belgium and the UK.20

The European Medicines Agency (EMA) issued a decision (P/0055/2021) on January 27, 2021, granting a product-specific waiver for a paediatric investigation plan (PIP) concerning an oral tablet formulation combining Nefopam (hydrochloride) and paracetamol, intended for the treatment of acute pain.39

C. Asia (China and other relevant regions)

Nefopam has a history of use in Asia. It was approved in China for the indication of pain as early as December 31, 1984.47 It is also reported to be used in other East Asian countries.47

Clinical research and trials involving Nefopam have been conducted in several Asian countries. For instance, studies have taken place in Thailand investigating its use for cancer pain and for postoperative pain management in spine surgery patients.48 Similarly, clinical trials have been carried out in South Korea, evaluating Nefopam for postoperative pain in kidney donors and following laparoscopic cholecystectomy.29

The stark contrast in regulatory status—not approved in the United States versus approved and used in many European and some Asian nations—suggests differing interpretations of Nefopam's overall risk-benefit profile by various national regulatory agencies. This divergence could also be influenced by historical factors, such as its introduction into certain markets prior to the universal adoption of current, more stringent drug approval processes, or by the specific data packages submitted for review in each region. The off-label oral use of the intravenous formulation in France, as reported before wider availability of oral forms in that market [20], points to a perceived clinical need or preference for Nefopam by practitioners that may have outpaced formal drug formulation development and approval for that specific route in that country. Such practices often emerge when clinicians seek therapeutic alternatives and adapt existing formulations to meet patient needs, highlighting potential gaps in the pharmaceutical market.

VIII. Conclusion and Future Perspectives

A. Summary of Nefopam's Profile

Nefopam is a unique, centrally-acting non-opioid analgesic characterized by a multi-modal mechanism of action that includes serotonin-norepinephrine-dopamine reuptake inhibition and modulation of voltage-gated ion channels. It has an established role in the management of acute pain, particularly in the postoperative setting, where its opioid-sparing benefits are clinically significant. However, the evidence supporting its use in chronic pain conditions is more variable, and it is not universally recommended by major clinical guidelines for this indication.

Nefopam possesses a distinct side effect profile, with common effects on the central nervous, gastrointestinal, and autonomic systems (including anticholinergic and sympathomimetic manifestations). This necessitates careful patient selection, appropriate dose adjustments, and diligent monitoring, especially in vulnerable populations such as the elderly and those with renal or hepatic impairment. The significant regional variations in its regulatory approval underscore the differing assessments of its risk-benefit balance globally.

B. Unmet Needs and Areas for Future Research

The current body of evidence suggests that Nefopam is a useful analgesic in specific contexts but is not without limitations. Its unique non-opioid mechanism offers advantages, particularly its opioid-sparing capacity. However, its side effect profile and the existing gaps in evidence for certain indications, such as its role in chronic pain as viewed by NICE and SIGN guidelines [10], restrict its universal applicability. Future research should aim to better define its therapeutic niche and optimize its clinical use.

Several areas warrant further investigation:

• Mechanism of Action: A more complete elucidation of its complex mechanism, including the relative contributions of its SNDRI activity, ion channel modulation, and NMDA antagonism to both its analgesic effects and its side effect profile, is needed.
• Chronic Pain: Robust, large-scale, and well-designed clinical trials are required to definitively clarify Nefopam's efficacy, safety, and precise place in the therapeutic algorithm for various chronic pain conditions.
• Comparative Efficacy and Safety: More head-to-head comparative studies against other active analgesics, including NSAIDs, paracetamol, and newer non-opioid agents, across different pain types would be beneficial. These studies should focus on both short-term efficacy and long-term safety outcomes.
• Dosing Optimization: Research aimed at optimizing Nefopam dosing regimens for specific surgical procedures or distinct patient populations could help maximize its efficacy while minimizing adverse events such as injection site pain or CNS disturbances, as highlighted by studies showing dose-dependent effects and higher ED50 values in certain contexts.[28]
• Investigational Uses: Further exploration of its potential in promising off-label or investigational areas, such as neuropathic pain, Parkinson's disease, and specific types of visceral pain, should be pursued through well-designed randomized controlled trials.
• Abuse Potential: Although considered to have low abuse potential compared to opioids, reports of dependence and abuse [7] warrant further investigation into its centrally rewarding properties and the development of strategies to mitigate any such risks.
• Pediatric Use: If deemed ethically appropriate and clinically necessary, well-controlled pediatric studies are needed to establish safe and effective dosing guidelines for children, addressing the current data gap.
• Pharmacogenomics: Pharmacogenomic studies could help identify genetic variations that predict patient response to Nefopam or susceptibility to its adverse effects, allowing for more personalized pain management strategies.

The global disparity in Nefopam's regulatory approval and usage patterns may present challenges for international clinical trial collaborations and for the synthesis of a comprehensive global evidence base. This situation also raises considerations regarding equitable access to potentially beneficial non-opioid analgesic options for patients worldwide. Addressing these research areas will be crucial for refining the clinical role of Nefopam and maximizing its potential benefits in pain management.

Works cited

1. Nefopam - Wikipedia, accessed June 11, 2025, https://en.wikipedia.org/wiki/Nefopam
2. Nefopam | C17H19NO | CID 4450 - PubChem, accessed June 11, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Nefopam
3. 460636 Nefopam CAS: 13669-70-0, accessed June 11, 2025, https://www.usbio.net/biochemicals/460636/Nefopam
4. Nefopam (Fenazoxine) | Analgesic Agent - MedchemExpress.com, accessed June 11, 2025, https://www.medchemexpress.com/nefopam.html
5. Nefopam hydrochloride | Wnt/beta-catenin | Sodium Channel - TargetMol, accessed June 11, 2025, https://www.targetmol.com/compound/nefopam%20hydrochloride
6. (±)-Nefopam (hydrochloride) (CAS 23327-57-3) - Cayman Chemical, accessed June 11, 2025, https://www.caymanchem.com/product/38137/(%C2%B1)-nefopam-(hydrochloride)
7. Nefopam Hydrochloride 30 mg Film coated tablets - Summary of ..., accessed June 11, 2025, https://www.medicines.org.uk/emc/product/5005/smpc
8. About nefopam - NHS, accessed June 11, 2025, https://www.nhs.uk/medicines/nefopam/about-nefopam/
9. The uses of Nefopam medication | Vinmec, accessed June 11, 2025, https://www.vinmec.com/eng/blog/uses-of-nefopam-en
10. Use of nefopam for chronic pain – SPS - Specialist Pharmacy ..., accessed June 11, 2025, https://www.sps.nhs.uk/articles/use-of-nefopam-for-chronic-pain/
11. Rediscovery of Nefopam for the Treatment of Neuropathic Pain - ResearchGate, accessed June 11, 2025, https://www.researchgate.net/publication/261766129_Rediscovery_of_Nefopam_for_the_Treatment_of_Neuropathic_Pain
12. Nefopam – Knowledge and References - Taylor & Francis, accessed June 11, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Pharmaceutical_medicine/Nefopam/
13. Definition of nefopam hydrochloride - NCI Drug Dictionary, accessed June 11, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/nefopam-hydrochloride
14. Nefopam - wikidoc, accessed June 11, 2025, https://www.wikidoc.org/index.php/Nefopam
15. Nefopam = 98 HPLC 23327-57-3 - Sigma-Aldrich, accessed June 11, 2025, https://www.sigmaaldrich.com/BB/en/product/sigma/sml0909
16. CN102363610A - New method for synthesizing nefopam ..., accessed June 11, 2025, https://patents.google.com/patent/CN102363610A/en
17. Efficacy of nefopam in postoperative pain management: A ..., accessed June 11, 2025, https://japsonline.com/admin/php/uploads/4513_pdf.pdf
18. CN102924320B - Method for preparing nefopam intermediate I ..., accessed June 11, 2025, https://patents.google.com/patent/CN102924320B/en
19. Pharmacokinetics, distribution, metabolism, and excretion of the dual reuptake inhibitor [ 14 C]-nefopam in rats - ResearchGate, accessed June 11, 2025, https://www.researchgate.net/publication/296469425_Pharmacokinetics_distribution_metabolism_and_excretion_of_the_dual_reuptake_inhibitor_14_C-nefopam_in_rats
20. Nefopam prescribing preferences in French hospitals: results of a survey - PMC, accessed June 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9167477/
21. Efficacy of nefopam in postoperative pain management: A systematic review of opioid consumption - Journal of Applied Pharmaceutical Science, accessed June 11, 2025, https://japsonline.com/abstract.php?article_id=4513&sts=2
22. A meta analysis of efficacy and safety of nefopam for laparoscopic cholecystectomy pain management - PMC - PubMed Central, accessed June 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11954109/
23. Nefopam position statement - Derbyshire Medicines Management, accessed June 11, 2025, https://www.derbyshiremedicinesmanagement.nhs.uk/assets/Clinical_Guidelines/Formulary_by_BNF_chapter_prescribing_guidelines/BNF_chapter_4/Nefopam_position_statement.pdf
24. The effect of using nefopam in fentanyl-based intravenous patient-controlled analgesia on the incidence of postoperative nausea and vomiting in laparoscopic gynecological surgery - Medical Biological Science and Engineering, accessed June 11, 2025, http://www.embse.org/journal/view.html?doi=10.30579/mbse.2021.4.1.20
25. Synergism between oral paracetamol and nefopam in a murine ..., accessed June 11, 2025, https://repositori.upf.edu/items/faa416df-91bd-44e8-a6a3-b84b1577b3db
26. Full article: Paracetamol for Multimodal Analgesia, accessed June 11, 2025, https://www.tandfonline.com/doi/full/10.2217/pmt-2021-0116
27. en.wikipedia.org, accessed June 11, 2025, https://en.wikipedia.org/wiki/Nefopam#:~:text=Nefopam%20is%20used%20to%20treat,surgery%20or%20recovery%20from%20surgery.
28. Median effective dose of nefopam to treat postoperative pain in patients who have undergone laparoscopic cholecystectomy - PMC - PubMed Central, accessed June 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6136022/
29. Effect of Nefopam-Based Patient-Controlled Analgesia with and without Fentanyl on Postoperative Pain Intensity in Patients Following Laparoscopic Cholecystectomy: A Prospective, Randomized, Controlled, Double-Blind Non-Inferiority Trial - MDPI, accessed June 11, 2025, https://www.mdpi.com/1648-9144/57/4/316
30. Efficacy of Intraoperative Paracetamol and Nefopam Infusions in ..., accessed June 11, 2025, https://pubmed.ncbi.nlm.nih.gov/39859046/
31. Efficacy of Intravenous Nefopam, Dexmedetomidine, and ... - MedPath, accessed June 11, 2025, https://trial.medpath.com/clinical-trial/8282fb34fb5a6258/nefopam-dexmedetomidine-meperidine-post-spinal-shivering
32. Nefopam – Application in Therapy and Current Clinical Research, accessed June 11, 2025, https://clinicaltrials.eu/inn/nefopam/
33. Efficacy of Intraoperative Paracetamol and Nefopam Infusions in Addition to Transversus Abdominis Plane Block in Kidney Transplant Recipients - MDPI, accessed June 11, 2025, https://www.mdpi.com/1648-9144/61/1/65
34. Comparison of analgesic effectiveness between nefopam and propacetamol in living kidney donors following rectus sheath block after hand-assisted living donor nephrectomy: a prospective, randomized controlled trial - PubMed Central, accessed June 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11218207/
35. en.wikipedia.org, accessed June 11, 2025, https://en.wikipedia.org/wiki/Nefopam#:~:text=Nefopam%20is%20thought%20to%20have,surgery%20or%20recovery%20from%20surgery.
36. How and when to take nefopam - NHS, accessed June 11, 2025, https://www.nhs.uk/medicines/nefopam/how-and-when-to-take-nefopam/
37. Side effects of nefopam - NHS, accessed June 11, 2025, https://www.nhs.uk/medicines/nefopam/side-effects-of-nefopam/
38. Information for the user Nefopam Hydrochloride 30mg Film-coated Tablets nefopam Read all of this leaflet carefu, accessed June 11, 2025, https://www.medicines.org.uk/emc/files/pil.5005.pdf
39. EMEA-002877-PIP01-20 - paediatric investigation plan | European Medicines Agency (EMA), accessed June 11, 2025, https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-002877-pip01-20
40. The systematic review and meta-analysis evaluated the efficacy and ..., accessed June 11, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1305844/full
41. www.medicines.org.uk, accessed June 11, 2025, https://www.medicines.org.uk/emc/product/2357/smpc#:~:text=Nefopam%2030%20mg%20tablets%20are%20contraindicated%20in%20patients%20with%20hypersensitivity,%2Doxidase%20(MAO)%20inhibitors.
42. Nefopam Hydrochloride 30 mg film-coated tablets - (emc) | 2357, accessed June 11, 2025, https://www.medicines.org.uk/emc/product/2357/smpc
43. www.nhs.uk, accessed June 11, 2025, https://www.nhs.uk/medicines/nefopam/taking-nefopam-with-other-medicines-and-herbal-supplements/#:~:text=Cautions%20with%20other%20medicines&text=any%20medicine%20that%20makes%20you,make%20these%20side%20effects%20worse
44. Taking nefopam with other medicines and herbal supplements - NHS, accessed June 11, 2025, https://www.nhs.uk/medicines/nefopam/taking-nefopam-with-other-medicines-and-herbal-supplements/
45. Nefopam - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed June 11, 2025, https://www.ncbi.nlm.nih.gov/books/NBK500905/
46. Public Notification: Pro ArthMax Contains Several Hidden Drug Ingredients - FDA, accessed June 11, 2025, https://www.fda.gov/drugs/medication-health-fraud/public-notification-pro-arthmax-contains-several-hidden-drug-ingredients
47. Nefopam Hydrochloride - Drug Targets, Indications, Patents - Synapse, accessed June 11, 2025, https://synapse.patsnap.com/drug/f9f664f3d1da4932acacfdc3388f1c95
48. Analgesic efficacy of nefopam for cancer pain: a randomized controlled study - PMC, accessed June 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7276938/
49. Perioperative Intravenous Nefopam on Pain Management and Ambulation after Open Spine Surgery: A Randomized Double-Blind Controlled Study, accessed June 11, 2025, https://www.asianspinejournal.org/m/journal/view.php?number=1542