28
VOLUME 10 NUMBER 1 • MARCH 2013
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
from two or more randomised clinical trials and includes duloxetine,
pregabalin, oxycodone CR, TCAs, amitryptiline and venlafaxine.
The expert panel of the American Academy of Neurology, the
American Association of Neuromuscular and Electro-diagnostic
Medicine, and the American Academy of Physical Medicine and
Rehabilitation based their recommendations on three class I and
five class II studies and recommended amitryptiline, and venlafaxine
and duloxetine in lessening the pain of PDPN.
4
Venlafaxine and
duloxetine also improved quality of life of patients. Venlafaxine was
superior to placebo when added to gabapentin. Only pregabalin
was recommended as a level A treatment.
5
There is insufficient evidence for the efficacy of desipramine,
imipramine, fluoxetine, or the combination of nortryptiline and
fluphenazine for the treatment of PDPN. SSRIs at this time should
be considered as third-line treatment. Topical therapies used early
on may be effective in some patients.
Most randomised, controlled trials have shown that drugs
generally have similar efficacy. Level A evidence in support of their
use includes tricyclic antidepressants, pregabalin, gabapentin,
tramadol, opioids, duloxitine, venlafaxine, topical lidocaine and
capsacin patches.
Combination therapy appears useful with tricyclic antidepressants
(gabapentin) and opiods (level A) but there are too few large-scale
comparative studies to compare the efficacy of these drugs. Future
trials will no doubt take into account co-morbidities, quality of
life, symptoms and signs using standardised tools, and attempt to
better define profiles that are effective when using specific drug
treatments.
Other options that have been tried and are under investigation
include:
Aldose reductase inhibitors: there have been many trials and
•
clinical attempts using this drug in the treatment of painful
neuropathy, but just as many failures, either because of toxicity
or lack of response to treatment.
Epelrestat prevents progression of peripheral neuropathy. Its
•
action is related to a reduction in the progression of advanced
glycation end-products.
VEGF-gene transfer is experimental treatment at this stage but
•
may show promise in the future.
Tricyclic antidepressants
See Fig. 7 for their mode of action.
NE + 5HT re-uptake inhibitor
•
Block Na
•
+
channels
Block cholinergic, histaminergic and
•
α
-adrenergic receptors.
Tricyclic antidepressants have the following adverse side effects:
cardiovascular-orthostatic hypotension and cardiac arrhythmias,
and drowsiness. They are also antagonists at the
α
1
-adrenergic
receptors, and anticholinergic and antihistaminic.
Tricyclic antidepressants should be used with caution in patients
with glaucoma, prostatic hypertrophy, cardiac conduction problems,
and a history of seizures.
Patients lacking cytochrome P
450
2D6 isoenzyme activity are
prone to the adverse effects of tricyclic antidepressants (and
venlafaxine) and have a weaker analgesic response to tramadol. In
my experience, drowsiness may be severe and persist well into the
following day.
For this reason, amitryptiline should be taken in the evening
and not before bedtime in order to limit this side effect. Starting
with 10 mg/day and increasing the dose gradually every few
days, to the therapeutic maximally tolerated effective dose is
advisable. In my view, the maximum dose that should be used is
75 mg/day, although some authors have suggested a dose as high
as 150 mg/day. Alternatives to amitriptyline include imipramine and
venlafaxine.
ECG screening is recommended in adults over 40 years of age.
Careful follow up of blood pressure (supine and erect) and heart
rate should also be carried out.
Anticonvulsants
Gabapentinbinds to the regulatory unit of neuronal calciumchannels
and blocks excessive excitability in the ascending pathways. The
therapeutic dose is 600 mg twice daily.
Pregabalin binds to an alpha-2D subunit of voltage-gated Ca
2+
channels, affects Ca
2+
influx at the presynaptic terminals in hyper-
excited neurons, and reduces release of excitatory neurotransmitters.
The effective dose is 75–300 mg bid. It is effective in 23–26% of
cases (50% reduction in pain) and is more effective than oxycodone
in reducing pain.
Sodium channel antagonists
Mexilitene is a third-line agent and its potency is equal to morphine,
gabapentin and amitriptyline for neuropathic pain. Side effects
include drowsiness, fatigue, nausea and dizziness.
Lacosamide
16
is an investigational drug for epilepsy and neuro-
pathic pain. It slowly inactivates voltage-gated sodium channels
and interacts with the collapsin response-mediator protein-2. It has
not been shown to be any better than placebo. These agents are
not recommended for the treatment of PDPN.
Opioids
Opioids act as agonists at
µ,
k
and
d
-opioid receptors. They inhibit
ascending transmission, activate descending inhibitory pathways
Figure 7.
Tricyclic antidepressants: mode of action.
