Pain- neuropathic

Question 1

TCA

Common indications

Answer 1

• Moderate to severe depression- where SSRI are ineffective
• Neuropathic pain

Question 2

TCA

MOA

Answer 2

• Tricyclic antidepressants inhibit neuronal reuptake of serotonin (5-HT) and noradrenaline from the synaptic cleft, thereby increasing their availability for neurotransmission.
• This appears to be the mechanism by which they improve mood and physical symptoms in moderate-to-severe (but not mild) depression and probably accounts for their effect in modifying neuropathic pain.
• Tricyclic antidepressants also block a wide array of receptors, including muscarinic, histamine (H1), α-adrenergic (α1 and α2) and dopamine (D2) receptors.
• This accounts for the extensive adverse effects profile that limits their clinical utility.

Question 3

TCA

Adverse effects

Answer 3

• Blockade of antimuscarinic receptors causes dry mouth, constipation, urinary retention and blurred vision.
• Blockade of H1 and α1 receptors causes sedation and hypotension.
• Cardiac adverse effects (multiple mechanisms) include arrhythmias and ECG changes (including prolongation of the QT and QRS durations).
• In the brain, more serious effects include convulsions, hallucinations and mania. Blockade of dopamine receptors can cause breast changes and sexual dysfunction and rarely causes extrapyramidal symptoms (tremor and dyskinesia).
• Tricyclic antidepressants are extremely dangerous in overdose, causing severe hypotension, arrhythmias, convulsions, coma and respiratory failure, which can be fatal.
• Sudden withdrawal of tricyclic antidepressants can cause gastrointestinal upset, neurological and influenza-like symptoms and sleep disturbance.

Question 4

TCA

Warnings

Answer 4

• Tricyclic antidepressants should be used with caution in people who are particularly at risk of adverse effects.
• These include the elderly, people with cardiovascular disease or epilepsy, and people with constipation, prostatic hypertrophy or raised intraocular pressure, which may be worsened by antimuscarinic effects.

Question 5

TCA

Interactions

Answer 5

• Tricyclic antidepressants should not be given with monoamine oxidase inhibitors as both drug classes increase serotonin and noradrenaline levels at the synapse and together they can precipitate hypertension and hyperthermia or serotonin syndrome (see Antidepressants, selective serotonin reuptake inhibitors). Tricyclic antidepressants can augment antimuscarinic, sedative or hypotensive adverse effects of other drugs.

Question 6

TCA

communication

Answer 6

• Advise patients that treatment will improve symptoms over a few weeks, particularly sleep and appetite.
• Discuss referring them for psychological therapy, which may offer more long-term benefits than drug treatment.
• Explain that they should carry on with drug treatment for at least 6 months after they feel better to stop the depression from coming back (2 years for recurrent depression).
• Warn them not to stop treatment suddenly as this may cause flu-like withdrawal symptoms and sleeplessness.
• When the time comes to stop treatment, they should reduce the dose slowly over 4 weeks. While patients may find some of the more common side effects unpleasant, they may tolerate them in favour of relieving depressive symptoms.
• Discussing at an early stage what side effects are expected may encourage patients to persist with treatment; at least until the full antidepressant effects are realised.

Question 7

Gabapentin and pregabalin

Common indications

Answer 7

1. Both drugs are used for focal epilepsies, usually as an add on treatment when other antiepileptic drugs provide inadequate control
2. Both drugs are used for neuropathic pain- first line for most neuropathic pains but second for diabetic neuropathic pain
3. Gabapentin is used for migraine prophylaxis
4. Pregabalin is used for generalised anxiety disorder

Question 8

Gabapentin and pregabalin

MOA

Answer 8

• From a structural point of view, gabapentin is closely related to γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain.
• However, its mechanism of action, although not completely understood, appears largely unrelated to GABA.
• It binds with voltage-sensitive calcium (Ca2+) channels, where it presumably prevents the inflow of Ca2+ and, in so doing, inhibits neurotransmitter release.
• This interferes with synaptic transmission and reduces neuronal excitability.
• Pregabalin is a structural analogue of gabapentin that probably has a similar mechanism of action.

Question 9

Gabapentin and pregabalin

Adverse effects

Answer 9

• Generally better tolerated than other antiepileptic drugs
• Main side effects are drowsiness, dizziness and ataxia, which usually resolves over the first few weeks of treatment

Question 10

Gabapentin and pregabalin

Warnings

Answer 10

• Renally excreted therefore dose should be reduced in renal impairment

Question 11

Gabapentin and pregabalin

Interactions

Answer 11

• Sedative effects are enhanced when used in combination with other sedative agents (e.g. BZs)
• Other than this, G&P are notable in having relatively few drug interactions

Question 12

Gabapentin and pregabalin

Communication

Answer 12

• Explain that you are offering a medicine which you anticipate will reduce the severity of their symptoms (e.g. the frequency of their fits).
• Explain that the medicine commonly causes some drowsiness or dizziness.
• For this reason, you will prescribe a low dose initially, then increase this gradually (make sure they are clear on the dosing instructions).
• Explain that these side effects should improve over the first few weeks. They should avoid driving or operating machines until they are confident that the symptoms have settled.