VOLUME 10 NUMBER 1 • MARCH 2013
29
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
and alter limbic system activity. There are significant risks using
this class of drug, including over-sedation, respiratory depression,
confusion and cognitive slowing.
Tramadol is a 5-HT releasing agent with widespread receptor
antagonist action in the CNS (antagonism to centrally acting
µ
-opioid
receptors, and to 5-HT, NMDA, nicotinic and M1 and M3 receptors).
It is also a weak inhibitor of 5-HT and noradrenaline re-uptake.
The effective therapeutic dose varies widely from patient to
patient and the lowest possible dose for relieving pain should be
used: 200–400 mg two to three times a day. Adverse side effects
include nausea and vomiting, dizziness, constipation, headache,
somnolence, excitability, pruritis, urinary retention, dependency
and potential abuse. Overdose on treatment is also a concern.
In a long-term tramadol–paracetamol trial, treatment-emergent
adverse side effects were transient and mild to moderate in
severity, with nausea recorded in 215 patients, dizziness in 16%,
somnolence in 16%, headache in 15% and constipation in 14%
(Janssen Pharmaceutical). In my experience, the side-effect profile
of tramadol is excellent if used at a low (but effective) dose and
treatment is carefully monitored.
Patients lacking cytochrome P
450
2D6 isoenzyme activity have a
weaker analgesic response to tramadol.
Selective serotonin–norepinephrine re-uptake inhibitors:
These
agents act by inhibiting 5-HT and noradrenaline re-uptake. Drugs in
this class include duloxetine and venlafaxine. The dose of duloxetine
is 60–120 mg/day and venlafaxine 75–225 mg/day. Side effects
include gastrointestinal symptoms: nausea, vomiting, diarrhoea
and constipation; pressor effects; weight gain with venlafaxine;
sexual dysfunction; and discontinuation reactions.
There have been many trials comparing duloxetine to placebo.
20-22
In most of these studies there was very little advantage using
duloxetine over the placebo group, i.e. the efficacy of the two
groups was about the same.
The duloxetine studies however did estimate a clinically important
difference on the scale by relating it to global assessments of
change in multiple studies of chronic pain. The clinical data derived
from these studies are difficult to interpret however because the
clinical importance of change from the baseline is not easy to
assess on the Likert scale, and there are no data-driven estimates
for clinically important differences in pain-intensity scales used for
chronic pain studies. The duloxetine studies however did estimate
a clinically important difference on the scale by relating it to global
assessments of change in multiple studies of chronic pain.
In a poster presentation at the 25th American Pain Society Annual
Scientific Meeting in San Antonio, Texas, inMay 2006,
22
Raskin showed
data that supported the notion that duloxetine was significantly better
than placebo in reducing neuropathic pain in diabetes at one week. It
maintained the improvement throughout the trial.
Duloxetine’s half-life
is about 12 hours (in plasma) and is highly
protein bound (> 90%). Once-daily dosing suggests that the
therapeutic effects may persist after the drug is cleared and the brain
concentration may differ from the plasma concentration. There is no
need for dose adjustment based on age, gender and/or smoking.
No specific laboratory tests are recommended prior to the use of
the drug, although duloxetine should ordinarily not be prescribed
to patients with substantial alcohol use or patients with any hepatic
insufficiency. Duloxetine does not affect HbA
1c
level, has no significant
long-term effect on blood pressure, has minimal long-term effect on
weight and has no increased risk of suicidal ideation.
Transient receptor-potential vanilloid receptor-1 (TRPV):
16,23
Capsaicin TRPV 1 is a non-selective cation channel abundantly
expressed in the C fibres. Modulating the TRPV 1 may be a
therapeutic option in PDPN. Capsaicin can desensitise TRPV 1
channels and relieve pain. It is the most widely studied drug in
this class in PDPN. Its use is limited to topical application due to
a narrow therapeutic index and side effects following systemic
administration. Because TRPV 1 causes an excitatory response prior
to desensitisation, it results in unwanted side effects and non-
compliance with the treatment. Antagonists of TRPV 1 may be
useful, but further trials are needed.
11,13,16
In a small trial using capsaicin, 22 patients with chronic severe
PDPN were randomised to 0.075% topical capsaicin or placebo for
eight weeks.
14
The results showed a reduction in pain intensity: 16
vs 4.1%; pain relief: 44.65 vs 23.25%; and a complete cure in 50%
of the cohort.
The analgesic is applied topically three to four times a day. The
major side effect is burning and reddening of the skin, which may be
intolerable to some patients. Long-term use may cause degeneration
of epidermal and dermal autonomic nerve fibres.
24-27
Alpha-lipoic acid
13,14
may be beneficial in reducing pain in PDPN.
One class I and two class II studies showed benefit, but pain was
not the pre-defined endpoint in these studies. The effect of the size
of pain reduction was 20–24% and superior to placebo.
14
Less commonly used or research options
TNF-alpha is one of a group of pro-inflammatory cytokines mediating
hyperalgesia in a diverse range of inflammatory and neuropathic
conditions. It is up-regulated following nerve injury. Cytokine
inhibitors and anti-inflammatory cytokines have an analgesic effect.
In painful neuropathy as opposed to non-painful neuropathy, TNF-
alpha and inerleukin-2 levels are increased.
TNF-alpha levels are higher in the serum of diabetic patients
and have been implicated in the aetiology of micro- and macro-
angiopathy. Hypertriglyceridaemia associated with small-fibre
neuropathy induces increased TNF-alpha production. Administration
of insulin and anti-oxidant therapy results in a reduction of TNF-alpha
and improvement of neuropathy. Antibodies to TNF-alpha cause
reduction in pain and allodynia. TNF-alpha causes up-regulation of
COX-2, PGE2, IL6 and CGRP and is involved in the regulation of
nerve growth factor.
Protein kinase-C inhibitors (PCK):
There is a well-established link
between PKC activation and endoneural ischaemia and neuropathy.
One of the drugs in this class is ruboxistaurin. However in one trial
where the drug was compared to a placebo group, there was
no difference in the primary endpoint, although the neuropathy
symptom score may have improved.
Actovegin
28,29
is a deproteinised haemoderivative produced
from calf’s blood by ultrafiltration. It stimulates oxygen absorption
and utilisation, and cellular energy metabolism. Actovegin exerts
an insulin-like effect: it stimulates glucose transport, pyruvate
dehydrogenase and glucose oxidation. It may improve hypoxia and
decrease nerve ischaemia.
A trial using 20 intravenous infusions of actovegin 2 000 mg/
day followed by 1 800 mg/day per os for 140 days was safe and
effective in improving neuropathic symptoms, vibration perception
threshold (VPT), sensory nerve function and mental health in type
2 diabetes patients with symptomatic polyneuropathy.
29
Decreasing
