Minocycline reduces experimental muscle hyperalgesia induced by repeated nerve growth factor injections in humans: A placebo‐controlled double‐blind drug‐crossover study

Abstract

Background Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double‐blind placebo‐controlled drug‐crossover trial, the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested. Methods An initial cohort (n = 10) received repeated injections (5 µg: days 0, 2 and 4) of nerve growth factor (NGF) in the flexor carpi ulnaris muscle of the forearm and pressure pain thresholds were collected at day 0 (control), day 7 (peak) and day 14 (recovery). A second cohort (n = 18) underwent an identical procedure, however, half received a placebo between days 0 and 7 before switching to minocycline from days 7 to 14 (P1/M2), while the remaining subjects received minocycline (day 0: 200mg then 100mg b.i.d. for 7 days) before switching to placebo (M1/P2). Results The initial cohort exhibited a diffuse muscular pain hypersensitivity with a decrease in pressure pain thresholds at day 7 before a partial return to normalcy at day 14. The P1/M2 treatment group exhibited an identical peak in hypersensitivity at day 7, however, after switching to minocycline in week 2 showed a significant reduction in muscle hyperalgesia compared with the initial cohort at day 14. The M1/P2 treatment group had significantly less (~43%) hyperalgesia at day 7 compared with the other groups. Conclusions The study indicates that the administration of minocycline can reduce experimentally induced muscle pain regardless of the time of administration. Significance In a double‐blind placebo‐controlled drug‐crossover study, the common antibiotic minocycline was found to reduce the muscle hyperalgesia induced by intramuscular injection of nerve growth factor. The results of the study showed that both concomitant (pre‐emptive) and delayed administration of minocycline can ameliorate the onset and facilitate the resolution of experimentally induced muscle hyperalgesia.

Modulation of Muscle Pain Is Not Somatotopically Restricted: An Experimental Model Using Concurrent Hypertonic-Normal Saline Infusions in Humans

“…Twenty-three healthy naïve participants aged 18–28 years (six females), with no reported history of musculoskeletal or neurological disorders, were recruited for this study. Participants were asked to abstain from intensive bouts of exercise for 48 h preceding the experiment so as not to sensitize the target muscles ( 15 ). Six participants took part in multiple arms of the study across different experimental sittings (30 experiments total), the inclusion of these participants in multiple study arms was random.…”

Targeting Oxidative Stress Involved in Endometriosis and Its Pain

“…This process is remarkable as it shares many characteristics like that of cancer cells including metastasis, invasion, and angiogenesis. Ectopic endometrial lesions may also produce a sensation of hyperalgesia or increased pain sensitivity in the presence of nerve growth factors [ 103 , 106 ]. These studies provide strong evidence that both neurogenic inflammation and pain-inducing ectopic lesions have an intricate role in inducing chronic pelvic pain in endometriosis [ 103 ].…”

Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain

“…Common minocycline doses were used for this study [ 38 ] Intramuscular injection of nerve growth factor 200 mg PO loading dose, followed by 100 mg PO twice daily for 7 days Reduces the muscle hyperalgesia induced by intramuscular injection of nerve growth factor in humans. Common minocycline doses were used for this study [ 39 ] Paclitaxel-induced acute pain 100 mg twice daily for 12 weeks Causes decrease in pain score and reduces fatigue in patients [ 40 ] Chemotherapy-induced neuropathic pain 100 mg twice daily for 6–7 weeks Reduces chemotherapy-induced pain and fatigue in patients with non-small cell lung cancer [ 41 ] Systematic review of human studies In most studies, 100 mg PO twice daily for several weeks to months Minocycline could have some potential for reducing neuropathic pain [ 42 ] Pioglitazone Antidiabetic drug Bone cancer pain model in rats 500 µg/day Ith for 7 days Treatment reduces mechanical hypersensitivity, possibly via activation of PPARγ and reduction of mTOR-signaling in spinal cord neurons. Likely off-target due to high dose Initial dose 15–30 mg/day PO then 15–45 mg/day PO [ 59 ] SNL in rats Pioglitazone alone (5–20 mg/kg IP) for 28 days or in combination with ceftriaxone (100 or 200 mg/kg IP) Ceftriaxone alone or in combination with pioglitazone (100 mg/kg each) reduces mechanical hypersensitivity, thermal hyperalgesia and cold allodynia.…”

“…In recent years, several small clinical trials have contributed to the concept of using minocycline as a treatment option for persistent pain in patients. For example, minocycline reduced bilateral muscular hyperalgesia and cutaneous cold allodynia caused by repeated intramuscular injections of hypertonic saline in healthy humans [ 38 ], and minocycline reduced muscle hyperalgesia induced by intramuscular injection of nerve growth factor (NGF) in humans in a small placebo-controlled double-blind clinical trial [ 39 ]. Moreover, minocycline treatment for 12 weeks caused a reduction of paclitaxel-induced acute pain and fatigue in cancer patients in a pilot study [ 40 ].…”