Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Abstract

Abstract. Nefopam, an analgesic drug, effectively elicits antinociception in the majority of noxious and thermal models in rodents. Acetaminophen is among the most commonly used analgesic and antipyretic drugs worldwide, either on prescription or over the counter. The present study aimed to investigate the analgesic activity of nefopam combined with acetaminophen, which was expected to maximize the potency of analgesia and decrease the dose of nefopam required. Three series of experiments, namely acetic acid-induced writhing tests in mice, hot plate tests in mice and tail flick tests in rats, were used to evaluate the analgesic effect. Initially, an optimum proportion of the two drugs, 3.5 mg/kg nefopam (N) + 60 mg/kg acetaminophen (A), was determined by orthogonal array design based on writhing response number. Subsequently, combinations of N and A (1.75 N + 30 A, 3.5 N + 60 A and 7.0 N + 120 A mg/kg) were determined to elicit antinociception in the writhing test (P<0.01 vs. normal saline control) in a dose-dependent manner. In the hot plate test, hot plate latencies up to 60 min after drug treatment were observed. The combination of 7.0 N + 120 A mg/kg exerted a greater cumulative antinociceptive effect throughout the observation period, with an area under the curve value of 1,156.95±199.30 area units (AU), compared with that achieved by 7.0 N mg/kg alone (632.12±62.38 AU). Furthermore, both monotherapy and compound therapy exhibited antinociception dose-dependently in the tail-flick test. However, a combination of 5.0 N + 84 A mg/kg exerted greater analgesic effect compared with 5.0 N mg/kg alone. The data obtained demonstrate that acetaminophen may enhance the antinociceptive activity of nefopam. Thus, coadministration of nefopam with acetaminophen warrants clinical evaluation.

Effect of nefopam in normal chickens and its relationship to hydrogen peroxide-induced oxidative stress

“…Nefopam is considered a non-narcotic analgesic medication used primarily to treat moderate to severe of acute or chronic nociception and to treat of a neuropathic pain disorder (1). Unlike narcotics; it does not causes addiction, respiratory depression and other deleterious effects related to narcotics therapy (1) and its analgesic activity may be potentiated by acetaminophen coadministration (2). By its centrally acting on the brain and spinal cord, nefopam could produce a better, more profound and reliable analgesia without causing respiratory depression similarly to morphine (1,(3)(4)(5).…”

Systematic Review of Systemic and Neuraxial Effects of Acetaminophen in Preclinical Models of Nociceptive Processing

“…These are summarized by pain models in the tables. Among them, 41 studies involved oral administration of acetaminophen, 66–105 38 studies with intraperitoneal injection, 73 , 76 , 86 , 102 , 106–140 13 studies with intrathecal administration, 74 , 87 , 121 , 132 , 141–147 12 studies with intravenous administration, 82 , 87 , 107 , 134 , 143 , 145 , 148–153 5 studies with intracerebroventricular administration 89 , 126 , 135 , 146 , 154 and with local subcutaneous in the paw, 82 , 126 , 135 , 155 , 156 7 studies with subcutaneous administration 124 , 141 , 157–161 and 1 study with rectal administration. 98…”

“… Ginger rhizome enhances anti-inflammatory and anti-nociceptive effects of APAP in mouse fibromyalgia Paw pressure Hot plate Tail flick Fibromyalgia syndrome Saline Mice/F Increased threshold 400 Montserrat-de la Paz et al 2018 66 2. Enhanced analgesic effects of nefopam with APAP Tail flick Hot plate Normal Saline Mice/F, M No change 42–168 Li et al 2018 107 Tail flick Hot plate Normal Saline Mice/F, M No change 60–240 3. Central dopaminergic system plays a role in analgesic action of APAP Hot plate Normal Saline Mice/M Increased escape latency 100 Bhagyashree et al 2018 68 4.…”

“… Synthesis and antinociceptive evaluation of bioisosteres and hybrids of naproxen, ibuprofen and APAP Formalin test Formalin Saline Rat/M Decreased behavior Phase 2 0.6–3.2 González-Trujano et al 2018 157 4. Enhanced analgesic effects of nefopam with APAP Writhing test Acetic acid Saline Mice/M Decreased behavior Dose dependent 42–168 Li et al 2018 107 5. APAP relieves inflammatory pain through CB1 in rostral ventromedial medulla Von Frey ITSP, extract IPLT zymosan Saline Mice/M Increased threshold Dose dependent 30–300 Klinger-Gratz et al 2017 67 7.…”

“…Delivery of irritants such as dilute acetic acid, capsaicin or phenyl benzoquinone into the peritoneal space will result in abdominal constriction in mice and rats, 86 , 107 , 121 reflecting activation of polymodal nociceptive afferent innervating the peritoneal wall. Distention of hollow organs will yield similar somatomotor response, and the threshold for generating these responses is lowered in the face of colonic inflammation.…”