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ANTIDEPRESSANTS
Sarah Andreae-Jones MB BS (Smith)
Patron of The Arachnoiditis Trust
England

 

Why use antidepressants?

 

If your GP or pain specialist suggests using this type of drug, it does NOT necessarily mean they think you are depressed. Arthur Lipman, PharmD, a Professor of Clinical Pharmacy at the University of Utah and editor of the Journal of Pharmaceutical Care in Pain & Symptom Control has studied chronic nonmalignant pain; he states: “We do not give the antidepressants to treat depression; these patients take relatively low doses, one-third to one-half the usual antidepressant dose for a tricyclic antidepressant.”

There have been numerous studies which have successfully demonstrated that tricyclic antidepressants are effective in treating neuropathic pain such as that seen in post-herpetic neuralgia, atypical facial neuralgia and diabetic neuropathy. McQuay([i]) stated that “compared with placebo, of 100 patients with neuropathic pain who are given antidepressants, 30 will obtain more than 50% pain relief, 30 will have minor adverse reactions and 4 will have to stop treatment because of major adverse effects.”

The Tricyclic group of antidepressants (TCAs) has a good reputation for relieving neuropathic pain. They are especially useful in patients who suffer from sleep disturbance secondary to pain (and one of the characteristics of neuropathic pain is that it is worse at night). The newer types of antidepressant such as Prozac, known as SSRIs, are much less effective although they may be useful if side-effects of TCAs are intolerable.

Previously it has been thought that TCAs are more effective against the burning pain rather than the lancinating pain, but now it is recognised that they help with both types.

Amitriptyline is the traditional choice of many doctors. It has sedative effects which can be exploited to aid sleep if it is given at night (although it may cause a hangover effect : see side-effects)

NNTs(numbers needed to treat: i.e. number of patients needed to be treated for 1 successful treatment ) for paroxetine are 5, fluoxetine 15.3, compared with between 2 and 3 for TCAs such as amitriptyline. (note: a high NNT denotes a poorly effective treatment).

Recent work by McCleane([ii]) has suggested that topical doxepin may have a useful role in treating neuropathic pain. Doxepin has previously been used in creams to treat pruritus (itching) and has been found to give rapid relief.

One of the deciding factors may be whether the proposed medication is sedative or activating.

For example, trazodone is highly sedative, which may be of help for improving sleep if given at night, whereas venlafaxine is an activating antidepressant which can cause anxiety, nervousness and insomnia.

Nefazodone (Serzone) is a calming antidepressant which is useful in treating fibromyalgia. Mirtazepine(Remeron) is sedating and helps to promote sleep restoration. It too has been useful in fibromyalgia.

Bupropion hydrochloride (wellbutrin) is unrelated to other antidepressants. In January 2000, news was broadcast about its use to treat nerve pain. Marilyn Semenchuk, Pharm.D, a neuropsychopharmacologist at the University of Arizona in Tucson, has treated 22 patients with wellbutrin and had about 68% success rate of significant pain relief. Wellbutrin has also been used to facilitate weight loss and to quit smoking. Details of this uncontrolled pilot study were published in March([iii]) and a larger, randomized, double-blind, placebo-controlled study is now underway.

Sindrup and Jensen([iv]) reported in 1999, based on placebo-controlled studies that showed more than 50% pain relief: that NNT* for SSRIs is 6.7 in treating diabetic neuropathy, as compared with 2.4 for tricyclic antidepressants (1.4 for imipramine). (* NNT=number-needed-to-treat: i.e how many patients need to be treated for 1 to be successful.)

 

 

DOSAGE:

Many authors advocate using very low dose antidepressants such as 10-30mg amitriptyline, but others have suggested a “therapeutic window” of 20-100mg for analgesic effects of amitriptyline.

Recently, higher doses of up to 150mg have been suggested. A sensible starting dose is 25mg(10mg in frail patients) at night, taken an hour before retiring. The aim should be to increase the dose weekly by increments of 25mg either until pain relief is achieved or adverse effects become troublesome. The maximum dose should be 150mg. Early morning drowsiness may be combated by taking the dose earlier in the evening.

Nortriptyline and desipramine are less sedating than amitriptyline so may be useful if the patient is unsteady or confused when getting up during the night or early in the morning.

Desipramine can be given 25mg at bedtime, increasing the dose to 50 mg after 3 days, then again to 75mg after a further 3 days. The maximum dose he recommends is 100mg (75mg in elderly patients).

If intolerable side-effects are experienced with TCAs and limit the increase up to an analgesic dose, the addition of a daytime SSRI may ameliorate matters. Paroxetine should be given at 40-60mg range. Also, tramadol (a centrally-acting analgesic) may be useful.

Venlafaxine is well tolerated and beneficial in some patients with neuropathic pain, at a dose of 25mg a day, increasing by 25mg every 3 days to a maximum of 150mg divided into 2 doses of 75mg.

 

 

TREATING CONCURRENT DEPRESSION:

Patients in chronic pain and who may have a variety of concomitant physical problems, may well experience depression secondarily. If using an SSRI such as sertraline or paroxetine note that the half-life of a TCA will be doubled . Fluoxetine has a very long half-life and may cause long-lasting drug interactions.

Onset of analgesic effect tends to be within one week (compare 10 days-3 weeks for antidepressant effect).

 

 

ADVERSE REACTIONS

TCAs are extremely dangerous in overdose, largely because of their cardiotoxic effects. SSRIs are much less dangerous.

Adverse effects that are intolerable or unmanageable lead to about 1 patient in every 30 discontinuing the treatment.

The commonest side-effects result from the anticholinergic effects of antidepressants:

Dry mouth and drowsiness are experienced by about one third of patients.

Less commonly:

Neurological/psychological side-effects (fairly rare):

Miscellaneous:

SSRIs have a different side-effect profile. They tend to have fewer (paroxetine)or no(fluoxetine, sertraline, fluvoxamine) anticholinergic effects.

The commonest side-effect is gastrointestinal distress (nausea, vomiting, diarrhoea), occurring in 20-40% of patients.

Some SSRIs such as venlafaxine may cause anxiety, agitation and possibly insomnia or nightmares. Venlafaxine may also cause a sustained increase in diastolic blood pressure, but this is generally not considered a contraindication to treating hypertensive patients.

Bupropion causes few cardiovascular effects, no anticholinergic effects, little sedation but is contraindicated in patients with seizure disorders.

Sexual dysfunction occurs in approximately 20-40% of patients on SSRIs (reports as high as 75% have resulted from direct interviews). The symptoms include anorgasmia, decreased libido and male erectile problems. These problems may persist despite lowering the dose and changing to a different drug such as bupropion, nefazodone or mirtazepine may be necessary. Alternatively, a measure such as a weekend “holiday” (SSRI taken on Thursday and not again until Sunday) may help.(this is only possible with drugs with a short half-life). Finally, adding a second SSRI may counteract the sexual side-effects of the original SSRI. Usually bupropion or buspirone are used given daily with the SSRI. Other agents such as cyproheptadine, sildenafil(Viagra) and dopamine agonists such as methylphenidate(Ritalin), amantadine(Symmetrel) and bromocriptine(Parlodel) may be given 1-2 hours before sexual intercourse.

 

 

WITHDRAWAL:

Whilst antidepressants are not regarded as addictive, abrupt cessation of usage of TCAs can precipitate symptoms ranging from nausea and vomiting, abdominal cramps, diarrhoea and chills lasting 3-5 days to up to 2 weeks of headache, malaise, muscle pains and paradoxical excitement.

After chronic use, gradual dose reduction may result in irritability, restlessness and dream and sleep disturbance, arising within 2 weeks of the reduction and tending to be temporary. Ideally, any dose reduction should be very gradual over a period of weeks.

Discontinuing SSRIs ca also result in flu-like withdrawal symptoms, which may include dizziness, headache, nausea, vomiting diarrhoea, movement disorders, insomnia, tremor, anorexia, electric shock-like sensations and depression.

 

 

DRUG INTERACTIONS:

Antidepressants such as TCAs are central nervous system depressants and may interact with other CNS depressants such as opiates (morphine etc.) or benzodiazepines and increase sedation and possibly respiratory depression.

Either SSRIs or TCAs, if given with tramadol may increase the risk of seizures.

TCAs should not be given with Monoamine oxidase inhibitors (MAOIs)

All antidepressants (except perhaps bupropion) magnify the effect of alcohol.

Anticholinergic agents or sympathomimetic drugs including epinephrine combined with local anaesthetics must be carefully supervised and dosage adjusted accordingly. Paralytic ileus (gut motion stopped) may occur in patients taking TCAs in combination with anticholinergic drugs such as oxybutinin (used for bladder dysfunction).

Antiepileptics: both TCAs and SSRIs lower the convulsive threshold; plasma concentration of carbamazepine is increased by fluoxetine and fluvoxamine. Anticonvulsant drugs may lower the plasma concentration of antidepressants.

TCAs may enhance the muscle relaxant effect of baclofen.

Both TCAs and SSRIs should not be used in conjunction with the antihistamine terfenadine as there may be an increased risk of arrhythmias.

As with opiates, grapefruit juice may affect the metabolism of antidepressants such as clomipramine, though the degree to which this is clinically relevant is as yet unkown.

 

 

SEROTONIN SYNDROME:

This may be caused by interaction between SSRI and MAO inhibitors or Tricyclics.

Features include:

It is important to exclude other possible causes of these symptoms such infection or metabolic disturbance.

Treatment is to discontinue or lower the SSRI medication and sometimes it is necessary to administer either Propranolol or Methysergide.

 

HERBAL PREPARATIONS:

St. John’s Wort has been found to be helpful in treating mild depression and some chronic pain patients may be tempted to try it. However, it may cause some unpleasant side-effects and also it should be noted that it acts like an SSRI and is therefore (a) unlikely to be of significant benefit and (b) could possibly cause agitation in much the same way as SSRIs might.

 

Dr. S. A. Andreae-Jones MB BS
Patron of the Arachnoiditis Trust
July 2000

 

 

[i] McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen PJ, Moore RA Pain 1996 Dec; 68(2-3):217-227 A systematic review of antidepressants in neuropathic pain.

[ii] McCleane GJ The Pain Clinic 1999;12:47-50 Topical doxepin hydrochloride reduces neuropathic pain: a randomised, doulbe blind, placebo controlled study.

[iii] Semenchuk MR, Davis B Clin J Pain 2000 Mar;16(1):6-11 Efficacy of sustained-release bupropion in neuropathic pain: an open-label study.

[iv] Sindrup SH, Jensen TS Pain 1999 Dec;83(3):389-400 Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action.