Diabetes vignette
A pain in the neck leading to hypoglycaemia
A
65-year-old man had had type 1
diabetes for six years, with meticulous attention to self-care,
frequent blood glucose testing, careful carbohydrate counting and a
basal bolus regimen of degludec and
Novorapid. (Figure 1.) He would generally have one mild hypo which he
could self-manage per fortnight, but
in clinic pointed out that he had had
just five hypos in two days. He wondered about the tramadol as the
cause: he had started on tramadol to
treat neck pain two days before the
hypos. We replaced the tramadol with
oramorph, and the hypos resolved.
Discussion
A nested case-control analysis within
the UK Clinical Practice Research
Datalink created a cohort of all patients
newly-treated with tramadol or codeine
for non-cancer pain between 1998 and
2012, and observed them for admissions for hypoglycaemia.1 Among
334 034 subjects, 1105 were hospitalised for hypoglycaemia; compared
with codeine, tramadol was associated
with a 50% increased risk of hypoglycaemia, particularly during the first 30
days of use. The frequency of hypoglycaemia was 7 per 10 000 users, but
these were hospitalisations for hypoglycaemia, and it is likely that less severe
hypos are not being recognised.2
The data also showed, not surprisingly,
that the subjects with admission
for hypoglycaemia were on average
elderly, with multiple comorbidities
and increased concomitant drug use.
A French pharmacovigilance study3
compared reports of hypoglycaemia
associated with tramadol, dextropropoxyphene and codeine; it was found
that there were 90 reports of hypos with
dextropropoxyphene, 53 with tramadol
and two with codeine -- although the
population at risk is not stated, it confirms the finding that hypos are more
common with tramadol than codeine;
also, some subjects became hypogly­
caemic without being on antidiabetic
agents, and hypos generally occurred
during the first few days of tramadol use.
It has been noted that tramadol
directly reduces hepatic gluconeogenesis and enhances peripheral
glucose utilisation in diabetic rats.2
200
PRACTICAL DIABETES VOL. 33 NO. 6
Figure 1. The patient’s meticulous monitoring diary
Tramadol is a commonly used analgesic; it is both a mu-opioid receptor
agonist and a re-uptake inhibitor of
serotonin and norepinephrine. The
opioid activity is due to both the parent
compound and the active metabolite
which is metabolised by CYP 2D6 and
gives inter-individual differences in
pharmacokinetics and clinical effects.
Tramadol increases risk of convulsions,
and should not be mixed with
other opiates, psychiatric medication
or drugs that raise serotonin levels.2,4
In the linked editorial,2 Nelson
and Juurlink wrote: ‘The increased
prescribing of tramadol most likely
reflects aggressive marketing coupled
with the perception that it is a safe
analgesic not prone to abuse. Whereas
the drug’s analgesic effects are at best
moderate, its toxic effects are dangerous and merit respect, particularly
when doses are escalated.’
A useful review of other drugs that
are known to cause hypoglycaemia5
includes alcohol, and pentamidine with
a high risk of hypoglycaemia which is
possible in the absence of diabetic hypoglycaemia treatment, and other agents
with a lesser risk of hypos such as chloroquine, ACE inhibitors, beta blockers,
salicyclates, and fluoroquinolones such
as ciprofloxacin. Recently, warfarin has
been shown to increase hypoglycaemia
rates in people on sulphonylureas,6 and
quinine is known to cause hypoglycaemia, particularly in the setting of renal
impairment causing quinine accumulation.7 The hypoglycaemic effects of
these drugs occur via various mechanisms, often in the same drug, e.g.
salicylate-induced hypoglycaemia may
be caused by increasing insulin secretion, increasing insulin sensitivity,
displacing sulphonylureas from protein-binding sites, and inhibiting renal
excretion.5 Another common drugrelated hypoglycaemia scenario occurs
when a patient’s dia­betes has been stabilised on glucocorticosteroids which are
then reduced or withdrawn.
Simon Croxson, MD, FRCP, Consultant
Physician, University Hospitals Bristol
NHS Foundation Trust, UK
Acknowledgement
I am most grateful to the patient for
sending me the scan of his record book.
Declaration of interests
There are no conflicts of interest.
References
References are available online at
www.practicaldiabetes.com.
COPYRIGHT © 2016 JOHN WILEY & SONS
Diabetes vignette
A pain in the neck and hypoglycaemia
References
1. Fournier JP, et al. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med 2015;175(2):186–93.
doi: 10.1001/jamainternmed.2014.6512.
2. Nelson LS, Juurlink DN. Tramadol and hypoglycaemia: one more thing to worry about. JAMA Intern
Med 2015;175(2):194–5. doi: 10.1001/jamaintern
med.2014.5260.
3. Bourne C, et al.; and the French Association of
Regional Pharmacovigilance Centres. Tramadol and
hypoglycaemia: comparison with other step 2 analgesic drugs. Br J Clin Pharmacol 2013;75(4):1063–7.
4: Grunenthal Ltd. SPC Zydol 50 mg capsules. https://
www.medicines.org.uk/emc/medicine/16371/SPC/
Zydol+50mg+Capsules/ updated 12 Feb 2015
[accessed 12 May 2016].
5: Vue MH, Setter SM. Drug-induced glucose alterations Part 1: Drug-induced hypoglycemia. Diabetes
Spectrum 2011;24(3):171–7.
6. Romley JA, et al. Association between use of warfarin with common sulfonylureas and serious hypoglycemic events: retrospective cohort analysis. BMJ
2015;351:h6223. doi: 10.1136/bmj.h6223.
7. Elliott J, et al. Oral quinine-induced hypoglycaemic
seizures. Pract Diabetes Int 2010;27(1):32–3.
200a
PRACTICAL DIABETES VOL. 33 NO. 6
COPYRIGHT © 2016 JOHN WILEY & SONS