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Therapeutic effects of diclofenac, pregabalin, and duloxetine on disuse-induced chronic musculoskeletal pain in rats.

ABSTRACT: The aim of this study was to clarify the mechanism of disuse-induced muscle hyperalgesia through the evaluation of the pharmacological behaviour of muscle hyperalgesia profiles in chronic post-cast pain (CPCP) rats with acute and chronic-phase mirror-image muscle hyperalgesia treated with diclofenac (NSAID), pregabalin (an inhibitor of Ca2+ channel ?2?), and duloxetine (SNRI). After 2 weeks of cast immobilization, the peak cross-sectional area and muscle wet weight of the ipsilateral soleus and gastrocnemius muscles decreased more significantly in CPCP rats than in untreated rats. Histological findings revealed disuse-induced muscle atrophy in CPCP rats. The blood biochemical parameters of CPCP rats in acute and chronic phases did not differ significantly from those of untreated rats. The diclofenac and pregabalin-treated groups exhibited no improvement in acute or chronic muscle hyperalgesia. In contrast, the duloxetine-treated group exhibited an improvement in acute muscle hyperalgesia, but showed no apparent effect on chronic muscle hyperalgesia on ipsilateral or contralateral sides. However, the chronic muscle hyperalgesia was reversed by intrathecal administration of DAMGO (a ?-opioid receptor agonist). The results suggest that chronic muscle hyperalgesia in CPCP rats did not result from an inflammatory mechanism, and there is only a low probability that it's caused by a neuropathic mechanism.

SUBMITTER: Ohmichi Y

PROVIDER: S-EPMC5818528 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Therapeutic effects of diclofenac, pregabalin, and duloxetine on disuse-induced chronic musculoskeletal pain in rats.

Ohmichi Yusuke Y Ohmichi Mika M Murai Nobuhito N Yasui Masaya M Takeshita Nobuaki N Oshibuchi Hidehiro H Naito Munekazu M Nakano Takashi T Sato Jun J

Scientific reports 20180219 1

The aim of this study was to clarify the mechanism of disuse-induced muscle hyperalgesia through the evaluation of the pharmacological behaviour of muscle hyperalgesia profiles in chronic post-cast pain (CPCP) rats with acute and chronic-phase mirror-image muscle hyperalgesia treated with diclofenac (NSAID), pregabalin (an inhibitor of Ca<sup>2+</sup> channel α2δ), and duloxetine (SNRI). After 2 weeks of cast immobilization, the peak cross-sectional area and muscle wet weight of the ipsilateral ...[more]

PMID: 29459641

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Project description:BackgroundPatients frequently fail to receive adequate pain relief from, or are intolerant of, first-line therapies prescribed for neuropathic pain (NeP). This refractory chronic pain causes psychological distress and impacts patient quality of life. Published literature for treatment in refractory patients is sparse and often published as conference abstracts only. The aim of this study was to identify published data for three pharmacological treatments: pregabalin, lidocaine plaster, and duloxetine, which are typically used at 2(nd) line or later in UK patients with neuropathic pain.MethodsA systematic review of the literature databases MEDLINE, EMBASE and CCTR was carried out and supplemented with extensive conference and grey literature searching. Studies of any design (except single patient case studies) that enrolled adult patients with refractory NeP were included in the review and qualitatively assessed.ResultsSeventeen studies were included in the review: nine of pregabalin, seven of the lidocaine plaster, and one of duloxetine. No head-to-head studies of these treatments were identified. Only six studies included treatments within UK licensed indications and dose ranges. Reported efficacy outcomes were not consistent between studies. Pain scores were most commonly assessed in studies including pregabalin; trials of pregabalin and the lidocaine plaster reported the proportion of responders. Significant improvements in the total, sensory and affective scores of the Short-form McGill Pain Questionnaire, and in function interference, sleep interference and pain associated distress, were associated with pregabalin treatment; limited or no quality of life data were available for the other two interventions. Limitations to the review are the small number of included studies, which are generally small, of poor quality and heterogeneous in patient population and study design.ConclusionsLittle evidence is available relevant to the treatment of refractory neuropathic pain despite the clinical need. There is a notable lack of high-quality comparative studies. It is evident that there is a need for future, high quality trials, particularly "gold-standard" RCTs in this refractory patient population.

Project description:PurposeDuloxetine and pregabalin are recommended as first-line treatments for diabetic peripheral neuropathic pain (DPNP). However, studies have not reported a direct comparison between duloxetine and pregabalin. We conducted a postmarketing, randomized, double-blind study to assess the noninferiority of duloxetine compared with pregabalin after 12 weeks of treatment in adult patients with DPNP in Japan (NCT02417935).Patients and methodsPatients (N = 303) with distal symmetrical DPNP were randomized to and were administered duloxetine (40-60 mg/day) or pregabalin (300-600 mg/day). The primary endpoint was the change from baseline in weekly mean of the 24-hour average pain score (numeric rating scale [NRS]). Noninferiority of duloxetine compared with pregabalin was assessed with the primary endpoint at week 12. Secondary measures, including night pain and worst pain, Brief Pain Inventory-Severity and Interference rating short form (BPI-SF), Clinical Global Impression of Improvement (CGI-I), Patient Global Impression of Improvement (PGI-I), and Neuropathic Pain Symptom Inventory (NPSI), health outcome measures (EuroQol 5-Dimension index and VAS), and safety were also assessed.ResultsFor the 24-hour NRS average pain score, the difference between the duloxetine and pregabalin groups was 0.072 (95% CI: - 0.295, 0.439), and the upper bound of the 95% CI (0.439) did not exceed the predefined noninferiority margin (0.51), at the end of the study period. For secondary outcome measures (night pain, worst pain, BPI-SF, CGI-I, PGI-I, NPSI) and health outcome measures, both the duloxetine and pregabalin treatment groups showed an improvement from baseline with no significant between-group difference. Duloxetine and pregabalin were well tolerated and the safety profiles were consistent with previously reported results.ConclusionThis study demonstrated the noninferior efficacy of duloxetine compared with pregabalin in the treatment of adult patients with DPNP. The safety analyses showed an acceptable tolerability based on safety profiles of duloxetine and pregabalin.

Project description:BackgroundDiabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP.MethodsOPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443.FindingsBetween Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway.InterpretationTo our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy.FundingNational Institute for Health Research (NIHR) Health Technology Assessment programme.

Dataset Information

Therapeutic effects of diclofenac, pregabalin, and duloxetine on disuse-induced chronic musculoskeletal pain in rats.

Publications

Therapeutic effects of diclofenac, pregabalin, and duloxetine on disuse-induced chronic musculoskeletal pain in rats.

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