Metamizole/dipyrone for the relief of cancer pain: A systematic review and evidence-based recommendations for clinical practice

Abstract

Background:

Dipyrone (metamizole) is one of the most widely used non-opioid analgesics for the treatment of cancer pain.

Aim:

Because evidence-based recommendations are not yet available, a systematic review was conducted for the German Guideline Program in Oncology to provide recommendations for the use of dipyrone in cancer pain.

Design:

First, a systematic review for clinical trials assessing dipyrone in adult patients with cancer pain was conducted. Endpoints were pain intensity, opioid-sparing effects, safety, and quality of life.

Data sources:

The search was performed in MedLine, Embase (via Ovid), and the Cochrane Library (1948–2013) and additional hand search was conducted. Finally, recommendations were developed and agreed in a formal structured consensus process by 53 representatives of scientific medical societies and 49 experts.

Results:

Of 177 retrieved studies, 4 could be included (3 randomized controlled trials and 1 cohort study, n = 252 patients): dipyrone significantly decreased pain intensity compared to placebo, even if low doses (1.5–2 g/day) were used. Higher doses (3 × 2 g/day) were more effective than low doses (3 × 1 g/day), but equally effective as 60 mg oral morphine/day. Pain reduction of dipyrone and non-steroidal anti-inflammatory drugs did not differ significantly. Compared to placebo, non-steroidal anti-inflammatory drugs, and morphine, the incidence of adverse effects was not increased.

Conclusion:

Dipyrone can be recommended for the treatment of cancer pain as an alternative to other non-opioids either alone or in combination with opioids. It can be preferred over non-steroidal anti-inflammatory drugs due to the presumably favorable side effect profile in long-term use, but comparative studies are not available for long-term use.

Keywords

Dipyrone palliative care neoplasms pain management review non-steroidal anti-inflammatory agents

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References

Nikolova

Tencheva

Voinikov

, et al. Metamizole: a review profile of a well-known “forgotten” drug. Part I: pharmaceutical and nonclinical profile. Biotechnol Biotec Eq 2014; 26: 3329–3337.

Kötter

Da Costa

Fässler

, et al. Metamizole-associated adverse events: a systematic review and meta-analysis. PloS ONE 2015; 10: e0122918.

Pogatzki-Zahn

Chandrasena

Schug

. Non-opioid analgesics for postoperative pain management. Curr Opin Anaesthesiol 2014; 27: 513–519.

Schug

Manopas

. Update on the role of non-opioids for postoperative pain treatment. Best Pract Res Clin Anaesthesiol 2007; 21: 15–30.

Ertin

Gunduz

Ulugol

. Contribution of nociceptin/orphanin FQ receptors to the anti-nociceptive and hypothermic effects of dipyrone. Acta Neuropsychiatr 2015; 27: 48–52.

Hinz

Brune

. Paracetamol and cyclooxygenase inhibition: is there a cause for concern? Ann Rheum Dis 2012; 71: 20–25.

Chandrasekharan

Dai

Roos

KLT

, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002; 99: 13926–13931.

Dos Santos

Dias

Teixeira

, et al. The analgesic effect of dipyrone in peripheral tissue involves two different mechanisms: neuronal K (ATP) channel opening and CB(1) receptor activation. Eur J Pharmacol 2014; 741: 124–131.

Escobar

Ramirez

Avila

, et al. Metamizol, a non-opioid analgesic, acts via endocannabinoids in the PAG-RVM axis during inflammation in rats. Eur J Pain 2012; 16: 676–689.

10.

Bausewein

Roller

Voltz

. Leitfaden Palliative Care - Palliativmedizin und Hospizbetreuung. Elsevier München, 5. Auflage, ISBN 9783437233135

11.

Sadusk

. The relationship of the food and drug administration to the practice of medicine and the aminopyrine-dipyrone problem. J New Drugs 1965; 5: 57–62.

12.

Huber

Andersohn

Sarganas

, et al. Metamizole-induced agranulocytosis revisited: results from the prospective Berlin Case-Control Surveillance Study. Eur J Clin Pharmacol 2015; 71: 219–227.

13.

Wissenschaftliches Institut der AOK (WIdO Research Institute). Arzneimittel, 2014, http://www.wido.de

14.

Schwabe

Paffrath

(eds). Arzneiverordnungs-report 2014: Aktuelle Daten, Kosten, Trends und Kommentare. Berlin: Springer, 2014.

15.

Hoffmann

Meinecke

Freitag

, et al. Who gets dipyrone (metamizole) in Germany? Prescribing by age, sex and region. J Clin Pharm Ther 2015; 40: 285–288.

16.

Kölzsch

Wulff

Ellert

, et al. Deficits in pain treatment in nursing homes in Germany: a cross-sectional study. Eur J Pain (London, England) 2012; 16: 439–446.

17.

Deutsches Ärzteblatt. Agranulozytose nach Metamizol – sehr selten, aber häufiger als gedacht (Aus der UAW-Datenbank), http://www.akdae.de/Arzneimittelsicherheit/Bekanntgaben/Archiv/2011/201108191.pdf (2011, accessed 1 October 2015).

18.

Sanofi. Fachinformation Novalgin® Injektionslösung: stand 05/2014. 2014.

19.

Liberati

Altman

Tetzlaff

, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009; 151: W65–W94.

20.

The Scottish Intercollegiate Guidelines Network (SIGN). SIGN 50: a guideline developer’s handbook. Edinburgh: The Scottish Intercollegiate Guidelines Network (SIGN), 2011.

21.

German Association of the Scientific Medical Societies (AWMF). AWMF guidance manual and rules for guideline development, http://www.awmf.org/en/clinical-practice-guidelines/awmf-guidance.html (2012, accessed 2 May 2016).

22.

Institute of Medicine (IOM). Clinical practice guidelines we can trust. Washington, DC: National Academies Press, 2011.

23.

Duarte Souza

Lajolo

Pinczowski

, et al. Adjunct dipyrone in association with oral morphine for cancer-related pain: the sooner the better. Support Care Cancer 2007; 15: 1319–1323.

24.

Rodríguez

Barutell

Rull

, et al. Efficacy and tolerance of oral dipyrone versus oral morphine for cancer pain. Eur J Cancer 1994; 30A: 584–587.

25.

Yalçin

Güllü

Tekuzman

, et al. A comparison of two nonsteroidal antiinflammatory drugs (diflunisal versus dipyrone) in the treatment of moderate to severe cancer pain: a randomized crossover study. Am J Clin Oncol 1998; 21: 185–188.

26.

Yalçin

Güllü

Tekuzman

, et al. Ketorolac tromethamine in cancer pain. Acta Oncol 1997; 36: 231–232.

27.

Moore

Derry

McQuay

, et al. Single dose oral analgesics for acute postoperative pain in adults. Cochrane Database Syst Rev 2011; 9: CD008659.

28.

Nabal

Librada

Redondo

, et al. The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer. A systematic review of the literature. Palliat Med 2012; 26: 305–312.

29.

Stockler

Vardy

Pillai

, et al. Acetaminophen (paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized, double-blind, placebo-controlled cross-over trial. J Clin Oncol 2004; 22: 3389–3394.

30.

Mercadante

Fulfaro

Casuccio

. A randomised controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: effects on dose-escalation and a pharmacoeconomic analysis. Eur J Cancer 2002; 38: 1358–1363.

31.

Hedenmalm

Spigset

. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol 2002; 58: 265–274.

32.

Wong

. A reappraisal of antipyretic and analgesic drugs. In: WHO pharmaceuticals newsletter. 2002, p. 15, http://apps.who.int/medicinedocs/en/d/Js2253e/5.html

33.

Hamerschlak

Montezuma

Bacal

, et al. Retrospective prevalence and incidence of drug-induced agranulocytosis in the city of São Paulo-Brasil. Rev Paul Med 1993; 111: 294–298.

34.

Blake

Winternitz

Geiger

, et al. Yale case studies: agranulocytic angina. Yale J Biol Med 1935; 7: 465–471.

35.

Bottiger

Westerholm

. Drug-induced blood dyscrasias in Sweden. Br Med J 1973; 3: 339–343.

36.

Bhaumik

. India’s health ministry bans pioglitazone, metamizole, and flupentixol-melitracen. BMJ 2013; 347: f4366.

37.

Risks of agranulocytosis and aplastic anemia. A first report of their relation to drug use with special reference to analgesics. The international agranulocytosis and aplastic anemia study. JAMA 1986; 256: 1749–1757.

38.

Kaufman

Kelly

Issaragrisil

, et al. Relative incidence of agranulocytosis and aplastic anemia. Am J Hematol 2006; 81: 65–67.

39.

Van der Klauw

Goudsmit

Halie

, et al. A population-based case-cohort study of drug-associated agranulocytosis. Arch Intern Med 1999; 159: 369–374.

40.

The Uppsala Monitoring Centre. The use of the WHO-UMC system for standardised case causality assessment, 2012. http://who-umc.org/Graphics/24734.pdf

41.

Risk of anaphylaxis in a hospital population in relation to the use of various drugs: an international study. Pharmacoepidemiol Drug Saf 2003; 12: 195–202.

42.

Andrade

Martinez

Walker

. Comparative safety evaluation of non-narcotic analgesics. J Clin Epidemiol 1998; 51: 1357–1365.

43.

Berruti

Salvidio

Saffioti

, et al. Noramidopyrine (Metamizol) and acute interstitial nephritis. Nephrol Dial Transplant 1998; 13: 2110–2112.

44.

Sánchez de la Nieta

Rivera

De la Torre

, et al. Acute renal failure and oligohydramnios induced by magnesium dypirone (metamizol) in a pregnant woman. Nephrol Dial Transplant 2003; 18: 1679–1680.

45.

Frechen

Zoeller

Ruberg

, et al. Drug interactions in dying patients: a retrospective analysis of hospice inpatients in Germany. Drug Saf 2012; 35: 745–758.

46.

Caraceni

Hanks

Kaasa

, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 2012; 13: e58–e68.