Repeated tender point injections of granisetron alleviate chronic myofascial pain--a randomized, controlled, double-blinded trial

Nikolaos Christidis, Shahin Omrani, Lars Fredriksson, Mattias Gjelset, Sofia Louca, Britt Hedenberg-Magnusson, Malin Ernberg, Nikolaos Christidis, Shahin Omrani, Lars Fredriksson, Mattias Gjelset, Sofia Louca, Britt Hedenberg-Magnusson, Malin Ernberg

Abstract

Background: Serotonin (5-HT) mediates pain by peripheral 5-HT3-receptors. Results from a few studies indicate that intramuscular injections of 5-HT3-antagonists may reduce musculoskeletal pain. The aim of this study was to investigate if repeated intramuscular tender-point injections of the 5-HT3-antagonist granisetron alleviate pain in patients with myofascial temporomandibular disorders (M-TMD).

Methods: This prospective, randomized, controlled, double blind, parallel-arm trial (RCT) was carried out during at two centers in Stockholm, Sweden. The randomization was performed by a researcher who did not participate in data collection with an internet-based application ( www.randomization.com ). 40 patients with a diagnose of M-TMD according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were randomized to receive repeated injections, one week apart, with either granisetron (GRA; 3 mg) or isotonic saline as control (CTR).

Results: The median weekly pain intensities decreased significantly at all follow-ups (1-, 2-, 6-months) in the GRA-group (Friedman test; P < 0.05), but not in the CTR-group (Friedman-test; P > 0.075). The numbers needed to treat (NNT) were 4 at the 1- and 6-month follow-ups, and 3.3 at the 2-month follow-up in favor of granisetron.

Conclusions: Repeated intramuscular tender-point injections with granisetron provide a new pharmacological treatment possibility for myofascial pain patients with repeated intramuscular tender-point injections with the serotonin type 3 antagonist granisetron. It showed a clinically relevant pain reducing effect in the temporomandibular region, both in a short- and long-term aspect.

Trial registration: European Clinical Trials Database 2005-006042-41 as well as at Clinical Trials NCT02230371 .

Keywords: 5-HT3-receptor; Granisetron; Human; Myofascial pain; Temporomandibular disorders.

Figures

Fig. 1
Fig. 1
CONSORT flowchart. Flowchart of the 40 participating patients throughout the study. The patients were referred for treatment of myofascial temporomandibular disorders
Fig. 2
Fig. 2
Pain drawings at baseline and follow-ups after treatment with either granisetron or control substance. The pain area at baseline (a) and follow-ups (1-month (b); 2-months, (c); 6-months (d)) after treatment with either granisetron (GRA-group) or control substance (isotonic saline; CTR-group) in 40 patients with myofascial temporomandibular disorders. The darker the area is the larger is the overlap from the different participants. The pain area decreased significantly in the GRA-group (Holm-Sidak’s test; P < 0.042) compared to baseline but not in the CTR-group (Holm-Sidak’s test; P > 0.065)
Fig. 3
Fig. 3
Scores for depression and nonspecific physical symptoms at baseline and follow-ups after treatment. Median (IQR) differences in scores for depression (a) and nonspecific physical symptoms (NSPhS) (b) in 40 patients with myofascial temporomandibular disorders before (baseline) and after repeated intramuscular tender-point injections with granisetron (GRA-group) or control substance (isotonic saline; CTR-group). Depression-scores are classified as normal (<0.535), moderate (0.535-1.105) and severe (>1.105), and the NSPhS-scores are classified as normal (<0.5), moderate (0.5-1) and severe (>1). There were no significant differences between groups in depression- or in NSPhS-scores at baseline. *Significant difference compared to baseline (Friedman-test with Dunn’s post-hoc test; P < 0.05)
Fig. 4
Fig. 4
Pressure pain thresholds at baseline and follow-ups after treatment with either granisetron or control substance. The mean (SEM) relative changes (%) of pressure pain threshold (PPT) in 40 patients with myofascial temporomandibular disorders before (baseline) and after repeated intramuscular tender-point injections with granisetron (GRA-group) or control substance (isotonic saline; CTR-group) over the a the right masseter muscle b the left masseter muscle and c over a reference point on the tip of the right index finger. There was no change in PPT after treatment with any of the substances

References

    1. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10(4):287–333. doi: 10.1016/j.ejpain.2005.06.009.
    1. Kelley P, Clifford P. Coping with chronic pain: assessing narrative approaches. Soc Work. 1997;42(3):266–277. doi: 10.1093/sw/42.3.266.
    1. Thomas SP. A phenomenologic study of chronic pain. West J Nurs Res. 2000;22(6):683–699.
    1. Okeson JP. Management of temporomandibular disorders and occlusion. 7. St. Louis, Missouri: Mosby, Elsevier Inc; 2013.
    1. LeResche L. Epidemiology of temporomandibular disorders: implications for the investigation of etiologic factors. Crit Rev Oral Biol Med. 1997;8(3):291–305. doi: 10.1177/10454411970080030401.
    1. Isong U, Gansky SA, Plesh O. Temporomandibular joint and muscle disorder-type pain in U.S. adults: the National Health Interview Survey. J Orofac Pain. 2008;22(4):317–322.
    1. Abud MC, dos Santos JF, da Cunha VP, Marchini L. TMD and GOHAI indices of Brazilian institutionalised and community-dwelling elderly. Gerodontology. 2009;26(1):34–39. doi: 10.1111/j.1741-2358.2008.00250.x.
    1. Zeitz KP, Guy N, Malmberg AB, Dirajlal S, Martin WJ, Sun L, Bonhaus DW, Stucky CL, Julius D, Basbaum AI. The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J Neurosci. 2002;22(3):1010–1019.
    1. Haus U, Spath M, Farber L. Spectrum of use and tolerability of 5-HT3 receptor antagonists. Scand J Rheumatol Suppl. 2004;119:12–18. doi: 10.1080/03009740410006961.
    1. Ernberg M, Hedenberg-Magnusson B, Alstergren P, Kopp S. The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia. Life Sci. 1999;65(3):313–325. doi: 10.1016/S0024-3205(99)00250-7.
    1. Ghafouri B, Larsson BK, Sjors A, Leandersson P, Gerdle BU. Interstitial concentration of serotonin is increased in myalgic human trapezius muscle during rest, repetitive work and mental stress - an in vivo microdialysis study. Scand J Clin Lab Invest. 2010;70(7):478–486. doi: 10.3109/00365513.2010.511257.
    1. Dawson A, Ghafouri B, Gerdle B, List T, Svensson P, Ernberg M (2014) Effects of Experimental Tooth Clenching on Pain and Intramuscular Release of 5-HT and Glutamate in Patients with Myofascial TMD. Clin J Pain. doi:10.1097/AJP.0000000000000154
    1. Ernberg M, Lundeberg T, Kopp S. Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals. Pain. 2000;85(1–2):31–39. doi: 10.1016/S0304-3959(99)00233-X.
    1. Ernberg M, Lundeberg T, Kopp S. Effect of propranolol and granisetron on experimentally induced pain and allodynia/hyperalgesia by intramuscular injection of serotonin into the human masseter muscle. Pain. 2000;84(2–3):339–346. doi: 10.1016/S0304-3959(99)00221-3.
    1. Sung D, Dong X, Ernberg M, Kumar U, Cairns BE. Serotonin (5-HT) excites rat masticatory muscle afferent fibers through activation of peripheral 5-HT3 receptors. Pain. 2008;134(1–2):41–50. doi: 10.1016/j.pain.2007.03.034.
    1. Christidis N, Kang I, Cairns BE, Kumar U, Dong X, Rosen A, Kopp S, Ernberg M. Expression of 5-HT3 receptors and TTX resistant sodium channels (Na(V)1.8) on muscle nerve fibers in pain-free humans and patients with chronic myofascial temporomandibular disorders. J Headache Pain. 2014;15:63. doi: 10.1186/1129-2377-15-63.
    1. Christidis N, Kopp S, Ernberg M. The effect on mechanical pain threshold over human muscles by oral administration of granisetron and diclofenac-sodium. Pain. 2005;113(3):265–270. doi: 10.1016/j.pain.2004.10.016.
    1. Christidis N, Ioannidou K, Milosevic M, Segerdahl M, Ernberg M. Changes of hypertonic saline-induced masseter muscle pain characteristics, by an infusion of the serotonin receptor type 3 antagonist granisetron. J Pain. 2008;9(10):892–901. doi: 10.1016/j.jpain.2008.05.002.
    1. Farber L, Stratz TH, Bruckle W, Spath M, Pongratz D, Lautenschlager J, Kotter I, Zoller B, Peter HH, Neeck G, Welzel D, Muller W, German Fibromyalgia Study G Short-term treatment of primary fibromyalgia with the 5-HT3-receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients. Int J Clin Pharmacol Res. 2001;21(1):1–13.
    1. Haus U, Varga B, Stratz T, Spath M, Muller W. Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain. Scand J Rheumatol Suppl. 2000;113:55–58.
    1. Bhosale UA, Khobragade R, Naik C, Yegnanarayan R, Kale J. Randomized, double-blind, placebo-controlled study to investigate the pharmacodynamic interaction of 5-HT3 antagonist ondansetron and paracetamol in postoperative patients operated in an ENT department under local anesthesia. J Basic Clin Physiol Pharmacol. 2015;26(3):217–222. doi: 10.1515/jbcpp-2014-0070.
    1. Manna V, Bolino F, Di Cicco L. Chronic tension-type headache, mood depression and serotonin: therapeutic effects of fluvoxamine and mianserine. Headache. 1994;34(1):44–49. doi: 10.1111/j.1526-4610.1994.hed3401044.x.
    1. Stratz T, Muller W. Treatment of chronic low back pain with tropisetron. Scand J Rheumatol Suppl. 2004;119:76–78. doi: 10.1080/03009740410007113.
    1. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J, Immpact Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1–2):9–19. doi: 10.1016/j.pain.2004.09.012.
    1. Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, Dimitrova R, Dionne R, Hertz S, Jadad AR, Katz NP, Kehlet H, Kramer LD, Manning DC, McCormick C, McDermott MP, McQuay HJ, Patel S, Porter L, Quessy S, Rappaport BA, Rauschkolb C, Revicki DA, Rothman M, Schmader KE, Stacey BR, Stauffer JW, von Stein T, White RE, Witter J, Zavisic S. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9(2):105–121. doi: 10.1016/j.jpain.2007.09.005.
    1. Muller W, Stratz T. Local treatment of tendinopathies and myofascial pain syndromes with the 5-HT3 receptor antagonist tropisetron. Scand J Rheumatol Suppl. 2004;119:44–48. doi: 10.1080/03009740410007032.
    1. Dworkin SF, LeResche L. Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique. J Craniomandib Disord. 1992;6(4):301–355.
    1. Headache Classification Subcommittee of the International Headache S The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(Suppl 1):9–160.
    1. Schulz KF, Altman DG, Moher D, Group C CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. Bmj. 2010;340:c332. doi: 10.1136/bmj.c332.
    1. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG, Consolidated Standards of Reporting Trials G CONSORT 2010 Explanation and Elaboration: Updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63(8):e1–37. doi: 10.1016/j.jclinepi.2010.03.004.
    1. Ho KY, Gan TJ. Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol. 2006;19(6):606–611. doi: 10.1097/01.aco.0000247340.61815.38.
    1. Gan TJ. Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same? CNS Drugs. 2005;19(3):225–238. doi: 10.2165/00023210-200519030-00004.
    1. Neafsey P, Ginsberg G, Hattis D, Sonawane B. Genetic polymorphism in cytochrome P450 2D6 (CYP2D6): Population distribution of CYP2D6 activity. J Toxicol Environ Health B Crit Rev. 2009;12(5–6):334–361. doi: 10.1080/10937400903158342.
    1. Stratz T, Farber L, Muller W. Local treatment of tendinopathies: a comparison between tropisetron and depot corticosteroids combined with local anesthetics. Scand J Rheumatol. 2002;31(6):366–370. doi: 10.1080/030097402320817103.
    1. Jensen MP, McFarland CA. Increasing the reliability and validity of pain intensity measurement in chronic pain patients. Pain. 1993;55(2):195–203. doi: 10.1016/0304-3959(93)90148-I.
    1. Farrar JT, Young JP, Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149–158. doi: 10.1016/S0304-3959(01)00349-9.
    1. Von Korff M, Ormel J, Keefe FJ, Dworkin SF. Grading the severity of chronic pain. Pain. 1992;50(2):133–149. doi: 10.1016/0304-3959(92)90154-4.
    1. McQuay HJ, Moore RA (1998) An evidence-based resource for pain relief. Oxford University Press, USA
    1. Louca S, Ernberg M, Christidis N. Influence of intramuscular granisetron on experimentally induced muscle pain by acidic saline. J Oral Rehabil. 2013;40(6):403–412. doi: 10.1111/joor.12046.
    1. Giamberardino MA, Affaitati G, Fabrizio A, Costantini R. Effects of treatment of myofascial trigger points on the pain of fibromyalgia. Curr Pain Headache Rep. 2011;15(5):393–399. doi: 10.1007/s11916-011-0205-3.
    1. Ernberg M, Lundeberg T, Kopp S. Effects on muscle pain by intramuscular injection of granisetron in patients with fibromyalgia. Pain. 2003;101(3):275–282. doi: 10.1016/S0304-3959(02)00334-2.
    1. Seide MF, Ulrich-Merzenich G, Fiebich B, Candelario-Jalil E, Koch FW, Vetter H. Tropisetron inhibits serotonin-induced PGE2 release from macrophage-like synovial cells in serum-free tissue culture. Scand J Rheumatol Suppl. 2004;119:33. doi: 10.1080/03009740410007005.
    1. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs. 1998;55(2):173–189. doi: 10.2165/00003495-199855020-00002.
    1. Schneider EM, Ma X, Stratz T, Muller W, Lorenz I, Seeling WD. Immunomodulatory function of the 5-HT3 receptor antagonist tropisetron. Scand J Rheumatol Suppl. 2004;119:34–40. doi: 10.1080/03009740410007014.
    1. Christidis N, Doepel M, Ekberg E, Ernberg M, Le Bell Y, Nilner M. Effectiveness of a prefabricated occlusal appliance in patients with temporomandibular joint pain: a randomized controlled multicenter study. J Oral Facial Pain Headache. 2014;28(2):128–137. doi: 10.11607/ofph.1216.
    1. Doepel M, Nilner M, Ekberg E, LE Bell Y. Long-term effectiveness of a prefabricated oral appliance for myofascial pain. J Oral Rehabil. 2012;39(4):252–260. doi: 10.1111/j.1365-2842.2011.02261.x.
    1. Nilner M, Ekberg E, Doepel M, Andersson J, Selovuo K, Le Bell Y. Short-term effectiveness of a prefabricated occlusal appliance in patients with myofascial pain. J Orofac Pain. 2008;22(3):209–218.
    1. Ekberg E, Nilner M. A 6- and 12-month follow-up of appliance therapy in TMD patients: a follow-up of a controlled trial. Int J Prosthodont. 2002;15(6):564–570.
    1. Ekberg E, Nilner M. Treatment outcome of appliance therapy in temporomandibular disorder patients with myofascial pain after 6 and 12 months. Acta Odontol Scand. 2004;62(6):343–349. doi: 10.1080/00016350410010063.
    1. Derry S, Wiffen PJ, Moore RA. Relative efficacy of oral analgesics after third molar extraction--a 2011 update. Br Dent J. 2011;211(9):419–420. doi: 10.1038/sj.bdj.2011.905.
    1. Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ. Topical NSAIDs for acute musculoskeletal pain in adults. Cochrane Database Syst Rev. 2015;6
    1. Derry S, Matthews PR, Wiffen PJ, Moore RA. Salicylate-containing rubefacients for acute and chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2014;11
    1. Ernberg M, Hedenberg-Magnusson B, List T, Svensson P. Efficacy of botulinum toxin type A for treatment of persistent myofascial TMD pain: a randomized, controlled, double-blind multicenter study. Pain. 2011;152(9):1988–1996. doi: 10.1016/j.pain.2011.03.036.
    1. Lindroth JE, Schmidt JE, Carlson CR. A comparison between masticatory muscle pain patients and intracapsular pain patients on behavioral and psychosocial domains. J Orofac Pain. 2002;16(4):277–283.
    1. Dworkin SF, Turner JA, Wilson L, Massoth D, Whitney C, Huggins KH, Burgess J, Sommers E, Truelove E. Brief group cognitive-behavioral intervention for temporomandibular disorders. Pain. 1994;59(2):175–187. doi: 10.1016/0304-3959(94)90070-1.
    1. Spath M, Stratz T, Farber L, Haus U, Pongratz D. Treatment of fibromyalgia with tropisetron--dose and efficacy correlations. Scand J Rheumatol Suppl. 2004;119:63–66. doi: 10.1080/03009740410007087.
    1. Christidis N, Nilsson A, Kopp S, Ernberg M. Intramuscular injection of granisetron into the masseter muscle increases the pressure pain threshold in healthy participants and patients with localized myalgia. Clin J Pain. 2007;23(6):467–472. doi: 10.1097/AJP.0b013e318058abb1.
    1. Samborski W, Stratz T, Mackiewicz S, Muller W. Intra-articular treatment of arthritides and activated osteoarthritis with the 5-HT3 receptor antagonist tropisetron. A double-blind study compared with methylprednisolone. Scand J Rheumatol Suppl. 2004;119:51–54. doi: 10.1080/03009740410007050.
    1. Garcia E, Godoy-Izquierdo D, Godoy JF, Perez M, Lopez-Chicheri I. Gender differences in pressure pain threshold in a repeated measures assessment. Psychol Health Med. 2007;12(5):567–579. doi: 10.1080/13548500701203433.
    1. Hrycaj P, Stratz T, Mennet P, Muller W. Pathogenetic aspects of responsiveness to ondansetron (5-hydroxytryptamine type 3 receptor antagonist) in patients with primary fibromyalgia syndrome--a preliminary study. J Rheumatol. 1996;23(8):1418–1423.
    1. Sherman JJ, LeResche L. Does experimental pain response vary across the menstrual cycle? A methodological review. Am J Physiol Regul Integr Comp Physiol. 2006;291(2):R245–256. doi: 10.1152/ajpregu.00920.2005.
    1. Merskey H, Bogduk N. Classification of chronic pain - Descriptions of chronic pain synromes and definitions of pain terms. 2. Seattle, USA: IASP press; 1994.
    1. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavand'homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JW, Wang SJ. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003–1007.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する