CURRENT TOPICS
SA JOURNAL OF DIABETES & VASCULAR DISEASE
140
VOLUME 7 NUMBER 4 • NOVEMBER 2010
it was found that 12.5% had never reported symptoms to their
doctor and nearly 40% had never received treatment for their
pain.
9
In a more recent cross-sectional study from Swansea in which
painful neuropathy was assessed by a symptoms questionnaire,
neurological history and examination, 26% of patients with type
2 diabetes were shown to have painful DPN. It was notable that
of these, 80% reported moderate to severe pain and this was
associated with curtailment of quality of life.
10
‘Insulin neuritis‘ and acute painful neuropathy of
poor glycaemic control
Acute painful neuropathies can occur in the context of: (1) rapid
glycaemic control, the so called ‘insulin neuritis‘
11,12
and (2) very
poor glycaemic control, typically in type 1 subjects sometimes
following diabetic ketoacidosis.
13
The term insulin neuritis is a
misnomer as the condition can also occur with rapid improvement
in glycaemic control after starting oral hypoglycaemic agents.
These acute syndromes are relatively rare compared to the chronic
painful neuropathy associated with DPN. In these acute painful
neuropathies there is a very rapid build-up of unpleasant sensory
symptoms within weeks rather than months, leading to persistent
lower limb burning pain, paraesthesiae and allodynia, with a
nocturnal exacerbation and depression.
12,13
There may also be
marked weight loss.
14
There are no motor signs and sensory loss
is often mild or absent.
12,13
In acute painful neuropathies there is
complete resolution of symptoms within a year.
15
Recent advances in the pharmacological management
of painful DPN
Despite the lack of controlled studies looking at the impact of
intensive glycaemic control in patients with painful DPN, there is a
general consensus among authorities in the field that good blood
glucose control should be the first step in the treatment of any
of the neuropathic syndromes associated with diabetes. Traditional
markers of macrovascular disease including hypertension, obesity,
hyperlipidaemia and smoking also appear to be independent
risk factors for DPN
2-4
and therefore attempts should be made to
address these by lifestyle change and pharmacotherapy.
Table 2 shows the range of pharmacological treatments for
painful diabetic neuropathy. Only two (duloxetine and pregabalin)
have been formally approved by the EMEA and the US FDA for the
treatment of painful DPN.
Tricyclic antidepressants
TCAs have been used to treat painful DPN for many years even
though they are not specifically licensed for it. Many randomised
controlled trials have demonstrated the efficacy of TCAs in painful
DPN.
16-18
They are also much cheaper than their newer comparators.
However, TCAs also have many side effects, chiefly anti-cholinergic
effects such as dry mouth, sweating, sedation and dizziness. As
there is nocturnal exacerbation of painful symptoms, treatment is
ideally started with a small dose (10–25 mg) of either amitripyline
or imipramine at night to help with sleep. The dose is then gradually
titrated depending on adverse events and efficacy. Caution
should be exercised in prescribing TCAs in those with established
cardiovascular disease as a recent study has shown an increased
risk of sudden cardiac death associated with TCA doses in excess
of 100 mg/day.
18
Selective serotonin noradrenaline reuptake inhibitors
Selective SNRIs relieve pain by increasing synaptic availability of
5-HT and noradrenaline in the descending pathways that inhibit
pain impulses.
The efficacy of duloxetine (an SNRI) in painful DPN has been
investigated in three identical trials and pooled data from these
show that the 60 and 120 mg/day doses are effective in relieving
painful symptoms, starting within a week and lasting the full
treatment period of 12 weeks.
19-21
Pain relief was experienced in
45–55% of patients, who achieved
≥
50% pain reduction that is
considered a clinically significant pain relief. The NNT to achieve at
least 50% pain reduction was 4.9 for 120 mg/day, and 5.2 for the
60 mg/day.
22
A particular advantage of duloxetine was that there
was no weight gain during prolonged treatment of up to a year.
Anticonvulsants
Gabapentin and pregabalin are
α
-2-
δ
subunit ligands and bind to
the subunit on the presynaptic neurone, thus reducing calcium flux
and hence reduced neurotransmitter release in the hyper-excited
neurone.
Gabapentin, titrated from 900 mg/day to 3 600 mg/day over
four weeks followed with another four weeks at the maximum
dose, has been compared with placebo
23
– 59.5% in the treatment
arm, 67% of whom received the highest dose of gabapentin,
achieved
≥
50% reduction in pain compared with 32.9% with
placebo. More recently, there have been several positive clinical
trials involving pregabalin in painful DPN. Data from seven clinical
trials involving pregabalin showed clear efficacy in management
of painful DPN with an NNT of 4.04 for the 600 mg/day and 5.99
for the 300 mg/day doses.
24
Only the 600 mg/day dosage showed
efficacy when administered b.i.d.
24
The median time to onset of a
sustained (
≥
30% at end point) 1-point improvement was four days
in patients treated with pregabalin at 600 mg/day and five days in
patients treated with pregabalin at 300 mg/day.
24
Opioid agonists
Opioids are generally used after a trial of TCAs, SNRIs and
α
-2-
δ
agonists. The weak opiate derivative tramadol has been found
effective in relieving neuropathic pain.
25
The strong opiod,
oxycodone, as a prolonged-release formulation has also been
effective in the management of neuropathic pain.
26
Although
clinicians are rather conservative in the use of opioid agonists,
Table 2.
Pharmacological treatment of painful DPN
TCAs
16–18
• Amitriptyline 25–150 mg/day
• Imipramine 25–150 mg/day
SNRIs
19–22
• Duloxetine 60–120 mg/day
Anticonvulsants
23,24
• Gabapentin 300–3 600 mg/day
• Pregabalin 900–600 mg/day
Opiates
25-28
• Tramadol 200–400 mg/day
• Oxycodone 20–80 mg/day
• Morphine sulphate SR 20–80 mg/day
