The Cochrane systematic review describes this quite succinctly: "There is moderate quality evidence that there is
a significant increase in minor adverse events with quinine compared to placebo but not in major adverse events. Overdosage,
however, is well documented to cause serious harm including death."
In the article “Nocturnal leg cramps”, BPJ 49 (Dec, 2012), we agree
that quinine is an effective treatment for reducing the frequency and severity of cramps, however, the unpredictable
and serious nature of its potential adverse effects mean that it is no longer recommended for this indication. After
reviewing the safety of quinine, Medsafe informed prescribers in 2007 that muscle cramps had been removed as an approved
indication,1 with a reminder again in 2010.2 Many other international medicine regulatory agencies, e.g. the United
States Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA), have issued similar
statements.3, 4 We acknowledge the correspondent's point of view, but believe that the risk of prescribing
quinine outweighs the benefit gained, for a condition, which although unpleasant, is not life-threatening.
The adverse effects associated with quinine can be grouped into three categories:5
- Dose-dependent reactions (occur with normal therapeutic use, but more common with higher doses): gastrointestinal
disturbance, tinnitus, vertigo, visual disturbance
- Overdose reactions (occur at doses higher than therapeutic level): cardiac arrhythmias, blindness, seizures
- Hypersensitivity reactions (occur at any time, and with any dose): thrombocytopenia, disseminated intravascular
coagulation, acute renal failure, haemolytic uraemic syndrome
Other risk factors for using quinine, particularly in elderly people, include renal impairment, medicine interactions
(e.g. digoxin, anticoagulants, phenothiazines) and memory loss which increases the potential for medicine administration
errors and overdose.5
The Cochrane review in 2010 included 23 trials with 1586 participants (of which 58% were from five unpublished studies).
It was concluded that compared to placebo, quinine reduced the number of muscle cramps over two weeks by 28%, reduced
intensity by 10% and reduced the days on which cramp occurred by 20%. Cramp duration was not significantly reduced.5 The
review also found that although more minor adverse effects occurred with quinine compared to placebo, there was no significant
difference in risk of major adverse reactions between quinine and placebo.5 However, the occurrence of major,
life-threatening adverse effects with quinine is rare – one patient had an event (thrombocytopenia) out of the 1103
participants for which data was available.5 Had there been more participants able to be studied, and the
power of the study greater, a different conclusion may have been reached.
The authors of the Cochrane review summed this up with the following: “On the basis of these [number of adverse events],
quinine appears to be reasonably safe, but it is not possible to accurately calculate the true incidence of serious
or life-threatening side effects which are rare…It is however on the basis of these serious adverse effects that the
FDA has banned the marketing of quinine for muscle cramps and that the American Academy of Neurology has recommended
in their report that it only be used as a last resort in intractable cramps and with close monitoring…Major adverse
events are rare but can be serious or fatal so that in some countries prescription of quinine is severely restricted.”5
The main problem when weighing up the risks and benefits of using quinine is that the most serious adverse effects
are due to hypersensitivity reactions, which are not dose-dependent, and may occur rapidly, after taking quinine for
the first time, or after years of use. There is no current evidence which enables clinicians to predict which patients
will experience serious adverse effects.5
Since January, 2008 (i.e. after the Medsafe warning), the Centre for Adverse Reactions Monitoring (CARM) in New Zealand
has received 12 reports on quinine, six of which were for patients who had developed thrombocytopenia. Two of these
patients experienced life-threatening effects, and in one, haemorrhage occurred within 12 hours of their first dose
of quinine. The indication for prescribing quinine in all six reports was for muscle cramp.
When managing a patient with leg cramps, first rule-out underlying causes of the cramp or associated conditions such
as medicine use (e.g. diuretics, naproxen, statins, long-acting beta-2 agonists), chronic dehydration, structural disorders,
peripheral vascular disease, oesteoarthritis, diabetes or neurological disorder. There is limited evidence that exercise
and muscle stretching is effective in reducing symptoms.6, 7 A 2012 Cochrane review of non-pharmacological
treatments for leg cramps concluded that there is an urgent need for quality data on emerging treatments.8
Nortriptyline, diltiazem, orphenadrine citrate, verapamil or gabapentin may be considered for patients with severe,
intolerable symptoms, used at the lowest effective dose and discontinued if no benefit is observed.9, 10 However,
the treatment of leg cramps is an unapproved indication for the use of these medicines (with the exception
of orphenadrine citrate), and patients should be informed of the risks and consent to treatment (see:
of unapproved medicines”).
For further information see: “Nocturnal
leg cramps: is there any relief?” BPJ 49 (Dec, 2012).
ACKNOWLEDGEMENT: Thank you to Dr Ruth Savage, Senior Medical Assessor, CARM, for providing data and comment for the
preparation of this answer.
- New Zealand Medicines and Medical Devices Safety Authority (Medsafe). Quinine - not for leg cramps anymore. Prescriber
Update 2007;28(1). Available from: www.medsafe.govt.nz (Accessed Mar, 2013).
- New Zealand Medicines and Medical Devices Safety Authority (Medsafe). Quinine is not indicated for nocturnal leg
cramps. Prescriber Update 2010;31(4). Available from: www.medsafe.govt.nz
(Accessed Mar, 2013).
- U.S. Food and Drug Administration. FDA Drug Safety Communication: New risk management plan and patient Medication
Guide for Qualaquin (quinine sulphate). FDA, 2010. Available from: www.fda.gov
(Accessed Mar, 2013).
- Therapeutic Goods Administration. Cramps, quinine and thrombocytopenia. Medicines Safety Update 2011;2(4). Available
from: www.tga.gov.au (Accessed Mar, 2013).
- El-Tawil S, Musa T, Valli H, et al. Quinine for muscle cramps. Cochrane Database Syst Rev 2010;(12):CD005044.
- BMJ Best Practice. Muscle cramps. BMJ; 2011. Available from:
http://bestpractice.bmj.com/best-practice/monograph/569.html (Accessed Mar, 2013).
- Hallegraeff J, van der Schans C, de Ruiter R, de Greef M. Stretching before sleep reduces the frequency and severity
of nocturnal leg cramps in older adults: a randomised trial. J Physio 2012;58(1):17-22.
- Blyton F, Chuter V, Walter K, Burns J. Non-drug therapies for lower limb muscle cramps. Cochrane Database Syst
- Allen R, Kirby K. Nocturnal leg cramps. Am Fam Physician 2012;86(4):350-5.
- Garrison S, Allen G, Sekhon R, et al. Magnesium for skeletal muscle cramps. Cochrane Database Syst Rev 2011;(9):CD009402.