P&T News: November/December 2001
Jennifer R. Larson, Pharm.D., at time of writing, Specialized
Resident in Primary Care, Department of Pharmaceutical Care, and
Patrick G. Jensen, Pharm.D., at time of writing, Specialized Resident
in Primary Care, Department of Pharmaceutical Care
Peer Review Status: Internally Peer Reviewed by
Gregory C. Doelle, M.D., Associate Professor, Division of
Endocrinology, Department of Internal Medicine.
The pathogenesis of painful diabetic neuropathy is presumed to be multifactorial.4 The medications that have been used to treat diabetic neuropathy primarily target pain symptoms, perhaps by the release of endorphins or biogenic amines.5,6 There are no known cures for neuropathy, and therefore, treatment is only symptomatic. With an increased understanding of the pathogenesis of diabetic neuropathy, new medications may be developed to treat the etiology. Currently, prevention should be the focus of treatment. Hyperglycemia and/or rapid fluctuations in glucose levels have been shown to decrease pain tolerance.7 The DCCT trial showed that tight glycemic control can delay the onset and slow the progression of neuropathy in insulin-dependent diabetics.8 The UKPDS trial also suggests that intensive glucose control in type 2 diabetics may reduce the occurrence of microvascular complications, including neuropathy.9 Nonpharmacologic therapy such as stretching exercises should be encouraged to offer relief of pain.3 Electrotherapy is another alternative, as it may benefit some patients who cannot tolerate or do not respond fully to medications.10,11 If these therapies do not completely resolve the patient's symptoms, treatment with medications may be considered. Drug treatment primarily includes antidepressants, anticonvulsants, and capsaicin. This article will focus on tricyclic antidepressants and gabapentin, the most commonly used medications.
TRICYCLIC ANTIDEPRESSANTS
Tricyclic antidepressants are the most widely studied agents for
the treatment of diabetic neuropathy. They inhibit the reuptake of
serotonin and norepinephrine to varying degrees in the central
nervous system; this is thought to have an inhibitory effect on
nociceptive pathways.5,6 Tricyclic antidepressants can be
divided into two groups -- tertiary and secondary amines.
Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine
are tertiary amines that block serotonin reuptake more than
norepinephrine reuptake. Secondary amines, including desipramine,
nortriptyline, and protriptyline, block norepinephrine reuptake more
than serotonin reuptake. This may help to explain some of the
differences between the agents.
Pharmacokinetic Properties
Tricyclic antidepressants are highly protein-bound. They are
metabolized in the liver by the CYP-450 system. Several isoenzymes
are involved, including 1A2, 2D6, 3A4, and 2C9/19. The tricyclic
antidepressants are metabolized to active metabolites. The half-lives
range from 6 to 39 hours and may be increased in patients with liver
impairment.
Efficacy
Max et al12 performed a double-blind, randomized,
crossover study in 29 patients 36 to 71 years of age. They compared
amitriptyline 25 mg per day, titrated up to 150 mg per day
over 3 weeks, to active placebo in the treatment of diabetic
neuropathy. Patient evaluation was conducted at 6 weeks by pain diary
and global assessment. Patients were also assessed for depression.
Amitriptyline significantly reduced pain in 79% of patients versus 3%
in control, while 17% of patients reported no difference between the
treatment phases. Both depressed and non-depressed patients had a
reduction in pain with amitriptyline, indicating that pain relief was
separate from the effect on mood. The mean dose of amitriptyline was
90 mg at bedtime and higher doses were linearly associated with
greater pain relief. Serum levels, however, did not correlate with
reduction in pain intensity.
Desipramine was compared to active placebo by Max et al13 in a double-blind, crossover trial. Twenty patients 21 to 71 years of age received desipramine 12.5 mg per day, titrated to 250 mg per day over 4 weeks, or active placebo. The mean dose of desipramine was 201 mg per day. Pain was evaluated by pain diary, global pain rating, and a pain intensity category scale. Patients were also assessed for depression. Desipramine was shown to be significantly superior to placebo for the primary outcome measure of mean pain intensity diary scores at 5 and 6 weeks. Fifty-five percent of patients taking desipramine categorized overall pain relief at 6 weeks as moderate or better, compared to 10% with placebo. Patients who had failed amitriptyline in the past also showed pain relief. Both depressed and non-depressed patients had pain relief.
Amitriptyline was compared to desipramine in a double-blind, crossover study.14 Thirty-eight patients 20 to 84 years of age received amitriptyline (mean dose 105 mg per day) or desipramine (mean dose 111 mg per day). Pain diaries and global pain relief ratings were used to evaluate pain. There was no significant difference in pain scores between the two drugs at 6 weeks. Seventy-four percent of patients reported moderate or greater pain relief with amitriptyline and 61% with desipramine.
Desipramine was also compared to clomipramine and placebo in a double-blind, crossover study.15 Nineteen patients 29 to 78 years of age received clomipramine 50 to 75 mg per day or desipramine 50 to 200 mg per day. A six-item observer and self-rating neuropathy scale was used to assess treatment at 2 weeks. When each medication was compared to placebo, scores were significantly improved in the clomipramine group while there was only a trend toward significance in the desipramine group. There were no significant differences between clomipramine and desipramine. Median reductions (improvements) in observer scores were 39% (95% CI 27-79%) for clomipramine and 32% (95% CI 0-46%) for desipramine when compared to placebo.
Kvinesdal et al16 compared imipramine to placebo in a fixed-dose, double-blind, crossover study in the treatment of diabetic neuropathy. Imipramine was titrated from 50 to 100 mg per day over 1 week in 12 non-depressed patients 30 to 75 years of age. Patients were evaluated at 5 weeks by a six-item scale and global assessment. There was no significant difference in the symptom scores, while global assessment showed statistical improvement in 58% of patients on imipramine versus no patients on placebo. Improvement was seen as early as 1 week. Serum concentrations were found to be higher in the patients who responded to imipramine.
A similar study was done by Sindrup et al17 that included 9 non-depressed patients, 40 to 59 years of age. The investigators used target concentrations of imipramine plus desipramine (400 to 600 nM) to guide the dose, which ranged from 125 to 225 mg per day. Eight patients (89%) reported significant improvement with imipramine at 3 weeks. A dose titration study18 was later performed which suggested that concentrations > 400 nM are needed for maximal efficacy. These studies show that dose titration is necessary; however, serum monitoring is probably not needed.
Nortriptyline has only been studied in combination with the antipsychotic fluphenazine for the treatment of diabetic neuropathy. Gomez-Perez et al19 compared this combination to placebo in a double-blind crossover study. Eighteen patients 30 to 73 years of age received nortriptyline and fluphenazine, titrated to 20 mg and 1 mg three times daily, respectively, over 2 weeks. Symptoms of pain and paresthesia were evaluated using the visual analog scale. Eighty-nine percent of patients had at least a 50% reduction of pain at 30 days. Pain reduction was not significant at 15 days.
A recent study also looked at the possibility of using topical doxepin 3.3% three times daily for the treatment of neuropathic pain.20 It showed a significant decrease in pain scores. Topical doxepin may offer an alternative treatment with fewer side effects, although systemic absorption is possible.21 Further studies are needed in diabetic neuropathy.
Of the tricyclic antidepressants, amitriptyline appears to be the most efficacious in the treatment of diabetic neuropathy when compared to placebo. The usefulness of nortriptyline remains to be determined since it has only been studied as combination therapy. For each of the tricyclic antidepressants, dose titration is necessary to achieve maximum response. Pain relief occurs regardless of patients' depression status.
Safety Issues
Because of their anticholinergic adverse effects, tricyclic
antidepressants should be used cautiously in patients with benign
prostatic hypertrophy, urinary retention, angle-closure glaucoma, and
cardiovascular disease. Patients with cardiovascular disease should
be closely monitored and have periodic ECG monitoring if tricyclic
antidepressants are used. Tricyclic antidepressants are
contraindicated in the acute recovery phase post-MI. They should also
be used cautiously in patients with a history of seizures since they
have the potential to decrease the seizure threshold. Elderly
patients may be more sensitive to the adverse effects of tricyclic
antidepressants22, in part due to their increased
potential for impaired hepatic function. Amitriptyline is on the
Beer's list of medications that are considered inappropriate in the
elderly due to its anticholinergic side effects.23
Imipramine and clomipramine also have many anticholinergic properties
and would impart a similar risk. Patients with impaired hepatic
function may have accumulation of the drug, and therefore, close
monitoring should be done. Patients who require mental alertness or
physical coordination for various activities should also use caution
with tricyclic antidepressants.
Adverse effects for these drugs relate to blockade of histamine H1, muscarinic, and a1-adrenergic receptors and include drowsiness, hypotension, dry mouth, blurred vision, constipation, urinary retention, memory dysfunction, dizziness, and reflex tachycardia.24 Tricyclic antidepressants also have quinidine-like properties which may result in cardiotoxicity. The tertiary amines (Table 1) are thought to have more anticholinergic side effects, cardiotoxicity, and impairment of memory and cognition.25
Withdrawal symptoms may occur if tricyclic antidepressants are abruptly stopped. Symptoms may include headache, dizziness, nausea, anxiety, myalgia, and chills. Even after gradual withdrawal, patients may experience restlessness, irritability, and sleep disturbances. If patients are on prolonged therapy with high doses, tricyclic antidepressants should be slowly tapered over 1 to 2 weeks or based on the patient's response.
Because they are metabolized by the CYP-450 system, there is the potential for drug interactions with agents that inhibit or induce these enzymes. Dosage adjustments may be necessary and patients should be closely monitored for side effects. Other drug interactions include additive CNS depression with alcohol, sedatives, and hypnotics. Clonidine's antihypertensive effects may be inhibited by tricyclic antidepressants.25 Blood pressure should be closely monitored if these are used in combination. Tricyclic antidepressants should not be used in combination with or within 2 weeks of monoamine oxidase inhibitors as this may increase the risk of seizures and serotonin syndrome.
Dosing
Tricyclic antidepressants should be started at a low dose and
slowly titrated to response and adverse effects. Anticholinergic
adverse effects may limit the dose that can be achieved. The lowest
effective dose should be used to minimize side effects. Table
2 shows the doses used in diabetic neuropathy.
GABAPENTIN
Gabapentin is an anticonvulsant that has been shown to be
effective in the treatment of diabetic neuropathy. Evidence suggests
gabapentin may increase GABA synthesis/facilitation or alter binding
to high voltage-active sodium and calcium channels.27
Pharmacokinetic Properties
Gabapentin has little affinity to plasma proteins, as it is 97%
unbound. Gabapentin's primary route of elimination is by renal
excretion and it is not appreciably metabolized in humans. Therefore,
the elimination rate constant is directly proportional to creatinine
clearance. The elimination half-life is 5 to 7 hours.
Efficacy
Backonja et al27 conducted a double-blind,
placebo-controlled study evaluating the effectiveness of gabapentin
versus placebo in the treatment of diabetic neuropathy. Gabapentin
was titrated from 900 mg per day to 3600 mg per day over 4 weeks in
165 patients (mean age 53 + 10.5 years). Sixty-seven percent
of patients achieved maximum doses, although no mean dose was
reported. At 8 weeks, 60% of patients on gabapentin had moderate or
greater pain relief, as measured by pain scores, compared to 33%
receiving placebo; this was a significant improvement. Pain reduction
was seen as early as 2 weeks in patients taking 1800 mg per day.
Sleep interference scores improved, and quality of life scores
regarding bodily pain, mental health, mood and vitality also improved
significantly when compared to placebo. It is noteworthy that
patients were excluded if they had a creatinine clearance of less
than 60 ml/min in order to avoid the necessary dosage adjustments
that would be required. Also, patients included in this study were
relatively young, which makes generalization to an elderly population
difficult.
Morello et al28 compared gabapentin 900 to 1800 mg per day (mean dose 1565 mg per day) to amitriptyline 25 to 75 mg per day (mean dose 59 mg per day) in 25 patients with diabetic neuropathy. The mean age of patients was 60.4 + 10.8 years. This study showed pain reduction in both groups at 6 weeks, although there was no statistically significant difference in intensity scores and global pain scores between the two medications. Weight gain occurred significantly more often with amitriptyline than gabapentin. Other adverse effects were similar among the two groups. These included sedation, dry mouth, dizziness, postural hypotension, ataxia, and lethargy. Although this study suggests no difference between amitriptyline and gabapentin, the results are limited since the doses of amitriptyline were lower than what had previously been shown to be effective.
Gabapentin has been shown to be effective in the treatment of diabetic neuropathy at doses greater than 900 mg/day. The current study comparing gabapentin to amitriptyline is difficult to interpret, as the mean amitriptyline dose is less than in previous studies. Further studies need to be performed to clarify these results.
Safety Issues
Gabapentin is generally well tolerated, as the discontinuation
rate in premarketing controlled clinical trials for seizures was
approximately 7%. The most common adverse effects are somnolence,
dizziness, ataxia, fatigue and nystagmus. Patients should be
cautioned that this medication might impair their cognition and
ability to operate machinery. In addition, gabapentin should be used
cautiously in patients with renal impairment and dosed accordingly.
Caution should be used when discontinuing gabapentin in patients with
a history of epilepsy, as rapid discontinuation may increase seizure
frequency. In the epilepsy patient population, gabapentin should be
discontinued gradually over 1 week.
Gabapentin has relatively few drug interactions; however, antacids have been shown to decrease the bioavailability of gabapentin by 20%. Therefore, it is recommended that gabapentin be given at least 2 hours after antacid administration.
Dosing
Studies have shown the minimal effective dose in the treatment of
diabetic neuropathy to be 900 mg per day. The usual initial dose is
300 mg three time daily. However, to minimize side effects, the dose
may be started at 300 mg per day and increased to 300 mg three times
daily over 3 days. The dose may be further titrated to response or
until limited by adverse effects. Due to gabapentin's extensive renal
elimination, dose adjustments should be made and caution should be
used in patients with renal impairment (Table
3).
Conclusion
Choosing which tricyclic antidepressant to use for the treatment
of diabetic neuropathy should be based on adverse effects and
efficacy. Since desipramine has the potential to cause less
anticholinergic side effects,24,29 it would be a
reasonable first option in the elderly.30 Nortriptyline
also has fewer anticholinergic side effects. However, it has only
been studied in combination with fluphenazine. It is not known
whether the combination of a tricyclic antidepressant with a
phenothiazine is superior to tricyclics alone,12 and
combination therapy increases the risk of adverse drug reactions;
therefore, it is not currently recommended. Further studies are
needed to determine nortriptyline's efficacy as monotherapy in the
treatment of diabetic neuropathy. Doses of tricyclic antidepressants
should be started low and slowly titrated to maximum doses as
patients are monitored for adverse effects and tolerability. Serum
concentrations probably do not need to be monitored except when
toxicity is suspected. Once a maximum dose is achieved, patients
should be maintained at that dose for at least 2 weeks to determine
the efficacy of the medication.
Gabapentin is considered a second-line agent as it costs substantially more and has not been shown to be superior to the tricyclic antidepressants. Gabapentin has a limited adverse effect profile when compared to the tricyclic antidepressants. However, somnolence and decreased renal function may limit its use. Patients should be given an adequate trial of the medication prior to determining efficacy. In the majority of patients, this consists of titrating to a dose greater than 900 mg per day and maintaining that dose for at least 2 weeks.
| Table 1. Comparison of Tricyclic Antidepressant Side Effects | ||||
|
|
Anticholinergic Effects | Cardiac Conduction Effects | Orthostatic Hypotension | Sedation |
|
Tertiary Amines |
||||
|
Amitriptyline |
+++++ | +++++ | +++++ | +++++ |
|
Clomipramine |
++++ | ++++ | ++ | ++++ |
|
Doxepin |
+++ | ++++ | +++ | +++++ |
|
Imipramine |
++++ | +++++ | +++++ | ++++ |
|
Trimipramine |
++++ | ++++ | +++ | ++++ |
|
Secondary Amines |
||||
|
Desipramine |
+++ | +++ | ++++ | +++ |
|
Nortriptyline |
++ | ++ | ++ | ++ |
|
Protriptyline |
++ | ++ | ++ | ++ |
|
+ Minimal; ++ Mild; +++ Moderate; ++++ Strong; +++++ Severe Adapted from reference 26 |
||||
| Table 2. Dosing of Tricyclic Antidepressants | ||
|
|
Doses Studied in Diabetic Neuropathy | Maximum Daily Dose |
|
Amitriptyline |
25 to 150 mg/day | 300 mg |
|
Clomipramine |
50 to 75 mg/day | 200 mg or 3 mg/kg |
|
Desipramine |
12.5 to 250 mg/day | 300 mg |
|
Imipramine |
50 to 225 mg/day | 300 mg |
| Table 3. Dosage Based on Renal Function | ||
| Creatinine Clearance (ml/min) | Total Daily Dose (mg/day) | Dose Regimen (mg) |
|
>60 |
1200 | 400 three times daily |
|
30-60 |
600 | 300 twice daily |
|
15-30 |
300 | 300 daily |
|
< 15 |
150 | 300 every other day |
|
Adapted from reference 25 |
||
References
DRUGS ADDED TO STOCK
ALLOPURINOL
Injection: 500 mg vial
Allopurinol injection (Aloprim® - Nabi) is a xanthine oxidase
inhibitor. It is indicated for the management of elevated serum and
urinary uric acid levels (i.e., prevention of uric acid nephropathy)
in patients who are receiving cancer chemotherapy and cannot tolerate
oral therapy.
Note: Prescribing restricted to Adult and Pediatric
Hematology/Oncology.
DROSPIRENONE/ETHINYL ESTRADIOL
Tablet: 3 mg/0.03 mg
Drospirenone 3 mg/ethinyl estradiol 0.03 mg tablets (Yasmin® -
Berlex) is an oral contraceptive. Drospirenone may be associated with
less water retention, less effect on blood pressure, and a more
favorable effect on cholesterol than other progesterone components of
oral contraceptives.
LIDOCAINE
Topical Patch: 5%
Lidocaine 5% topical patch (Lidoderm® - Endo) is indicated for
relief of pain associated with post-herpetic neuralgia.
NESIRITIDE
Injection: 1.5 mg vial
Nesiritide injection (Natrecor® - Scios) is a human B-type
natriuretic peptide manufactured by rDNA technology. It is indicated
for the treatment of acutely decompensated congestive heart failure
in patients who have dyspnea at rest of with minimal activity.
Note: Prescribing restricted to Cardiology; patient must be in a
monitored bed.
ZOLEDRONIC ACID
Injection: 4 mg vial
Zoledronic acid (Zometa® - Novartis) is a bisphosphonate that
inhibits osteoclastic bone reabsorption. It is indicated for the
treatment of hypercalcemia of malignancy.
ADDITIONAL ACTIONS
FENOFIBRATE TABLETS
A 54 mg and a 160 mg tablet (Tricor®) have been added to stock.
This product replaces fenofibrate micronized capsules, which were
discontinued by the manufacturer. Dosing conversions to achieve the
same plasma levels are as follows: 67 mg micronized capsule = 54 mg
tablet; 134 mg micronized capsule = 108 mg (two 54 mg tablets); 200
mg micronized capsule = 160 mg tablet.
RIBAVIRIN
A 200 mg capsule (Rebetol®) has been added to stock.
Note: The cost following each brief monograph is the UIHC acquisition
cost.
DRUGS DELETED FROM STOCK
ALUMINUM HYDROXIDE GEL (ALTERNAGEL®)
Deleted due unavailability of product. Amphojel® suspension
remains available.
BETHANECHOL INJECTION 5 mg/1 ml (URECHOLINE®)
Discontinued by the manufacturer. Bethanechol tablets are available.
DELAVIRDINE 100 mg TABLETS (RESCRIPTOR®)
Deleted due to low use. The 200 mg tablets are available.
EPTIFIBATIDE 200 mg/100 ml INJECTION (INTEGRILIN®)
20 mg/10 ml and 75 mg/100 ml strengths are available.
ETIDRONATE INJECTION (DIDRONEL®)
Deleted due to low use. Pamidronate injection is available.
FACTOR IX (KONYNE-80®) INJECTION
Discontinued by the manufacturer. Other Factor IX products are
available.
FENOFIBRATE MICRONIZED CAPSULES (TRICOR®)
Discontinued by the manufacturer. Fenofibrate tablets are available.
Dosing conversions to achieve the same plasma levels are as follows:
67 mg micronized capsule = 54 mg tablet; 134 mg micronized capsule =
108 mg (two 54 mg tablets); 200 mg micronized capsule = 160 mg
tablet. The cost of the tablets is comparable to the cost of the
micronized capsules.
FLUOROURACIL (FLUOROPLEX®) 1% SOLUTION
This product has been replaced by fluorouracil 2% solution.
INSECT TREATMENT (ANA-KIT®) KIT
Discontinued by the manufacturer. Epi-Pen® autoinjectors are
available.
SODIUM CHLORIDE 650 mg TABLETS
Deleted due to low use. Sodium chloride 1 gm tablets are available.
SODIUM TETRADECYL INJECTION (SOTRADECOL®)
Discontinued by the manufacturer. Ethanolamine injection is
available.
TRIAMCINOLONE 100 mg/5 ml INJECTION
Deleted due to low use. A 200 mg/5 ml strength is available.
VIDARABINE OPHTHALMIC OINTMENT (VIRA-A®)
Discontinued by the manufacturer.