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Pediatricians increasingly are recognizing a mandate to treat pain aggressively. Psychotropic drugs have new pediatric uses, broadening clinicians' options.
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Pediatricians increasingly are recognizing a mandate to treat pain aggressively. Psychotropic drugs have new pediatric uses, broadening clinicians' options.
Gone are the days when a pediatrician could guess a child's condition by knowing what class of medications he or she was taking. With the explosion of pharmacologic interventions and the search for quick remedies, medications formerly used in adults (and children for psychiatric conditions) are being tried for a variety of conditions in younger patients.1 At the same time, physicians are becoming increasingly aware of the pathophysiology of pain in children and adolescents and following a mandate to evaluate pain syndromes aggressively in all settings.
This article discusses some common psychotropic medicationsincluding tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and anticonvulsantsprescribed by pediatricians, neurologists, child psychiatrists, anesthesiologists, and others for chronic pain management in children and adolescents. Formal trials in children have not been performed for many of these drugs. However, if dosing recommendations for specified age ranges are included in the product labeling, Food and Drug Administration (FDA) approval for those ages is implied.2
Conditions in children for which clinicians might consider the agents discussed here include peripheral neuropathies, cancer pain, chronic abdominal pain, and migraines (see "Pain management: Case histories"). Using a comprehensive approach to assessing and treating pain, the clinician generally will need to prescribe some combination of medication and nonpharmacologic interventions. For the classes of drugs detailed here, Table 1 summarizes psychotropic formulations and indications, and Table 2 addresses adverse effects and monitoring requirements.3,4
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Pain is defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage."5 The clinician's goal should be to alleviate pain and distress while keeping medications to the minimum effective dose. The clinician also must try to avoid polypharmacy, which sometimes is impossible in the treatment of chronic pain.
A comprehensive approach to assessment and treatment of pain is paramount. A graded strategy for controlling cancer pain that the World Health Organization (WHO) recommends has become a model for pharmacologic treatment of other pain syndromes. This approach calls for a three-step ladder beginning with acetaminophen and nonsteroidal anti-inflammatory drugs, then adding opioids for more severe and chronic pain.6
The standard of care for acute and, particularly, chronic pain is multimodal and includes nonpharmacologic interventions such as cognitive strategies (distraction, guided imagery, hypnosis, education, and psychotherapy), behavioral therapies (relaxation and deep breathing, biofeedback, and behavior modification), and physical therapy in addition to medication management. Pediatricians can familiarize themselves with nonpharmacologic methods for relieving pain as well as nonsteroidal medications (which have proliferated), and opiate analgesia for acute and chronic pain in readily available recent reviews.79 Appropriate diagnosis and treatment of the comorbid depression and anxiety commonly seen in chronic pain conditions are critical.
Few pain studies in children have useful outcome measures beyond a decrease in magnitude and duration. In addition to taking detailed pain measurements, clinicians should monitor the patient's physical functioning, return to school or work, and health-care utilization when evaluating the efficacy of pain treatments.
TCAs have been a mainstay of pain treatment since the mid 1960s when amitriptyline first was demonstrated to benefit tension headaches and postherpetic neuralgia. Specifically, TCAs are thought to inhibit paroxysmal neuronal discharge and decrease the sensitivity of adrenergic receptors on injured nerve sprouts. TCAs such as imipramine, desipramine, clomipramine, and nortriptyline block the reuptake of norepinephrine (NE), and serotonin (5HT), particularly at the spinal dorsal horn synapses. TCAs also bind to histaminergic, cholinergic, and adrenergic receptors as well as block sodium and calcium channels, all mechanisms thought to be involved in pain regulation.10 The specificity of TCAs varies. For example, amitriptyline breaks down to nortriptyline as the active metabolite, which causes more blockade of histaminic receptors, leading to greater sedation and weight gain than nortriptyline alone.
More than 75 controlled trials in adults have shown that TCA efficacy in pain management varies by type of pain. Meta-analyses confirm that TCAs improve pain in diabetic neuropathy, postherpetic neuralgia, tension headaches, migraines, atypical facial pain, and possibly fibromyalgia. In contrast, TCAs have not been helpful in chronic back pain, irritable bowel syndrome, nonulcer dyspepsia, osteoarthritis, and rheumatoid arthritis.10
The use of TCAs in children with pain has been less extensively studied than in adults. Anecdotal experience suggests that TCAs are helpful in neuropathic pain syndromes secondary to childhood cancers caused by tumor invasion of nerves, chemotherapy-induced peripheral neuropathy, and radiation nerve damage.11 A prospective open-label trial of amitriptyline (up to 1 mg/kg) for migraine prophylaxis was effective and well tolerated.12
In children and adolescents, TCAs may cause fatigue and anticholinergic effects such as dry mouth, constipation, and, rarely, urinary retention. The symptoms frequently diminish with time and are better tolerated if the doses are advanced gradually. If difficulty falling asleep, low mood, or weight loss accompany pain, a TCA may be ideal. Neurologists more often prescribe amitriptyline; child psychiatrists, seeking less sedation and less weight gain, are more likely to prescribe nortriptyline. The literature favors amitriptyline, but nortriptyline is a useful alternative because it is more easily titrated with blood levels.
TCAs are generally given once a day at bedtime to aid with sleep. Initial monitoring includes complete blood count (CBC), electrocardiogram, and blood pressure since TCAs can lead to mild bone-marrow suppression, cardiac arrhythmias, tachycardia, and hypertension. Use TCAs with caution in patients with cardiac conduction abnormalities because of their potential to prolong the QTc interval.
An overdose of TCAs can be lethal, with symptoms appearing within four to six hours of ingestion. Serum drug levels do not necessarily predict outcome. TCAs should be given under careful supervision and may be dispensed in limited quantities if impulsive behavior is a concern.
Recent enthusiasm for SSRIs as antidepressants has led to their widespread use in children. Commonly used SSRIs include fluoxetine, paroxetine, sertraline, and citalopram, which, like TCAs, differ mainly in their side effect profiles. Recently, reports suggesting a possible increased risk of suicide among children and adolescents treated for depression with paroxetine have prompted an FDA review of the data (see "SSRIs and suicide").
The mechanism of therapeutic action of SSRIs for pain management is thought to be via potentiation of 5HT and NE nervous system pathways. SSRIs have been disappointing in managing pain in adults, however. A trial of citalopram and paroxetine for diabetic neuropathy showed only modest benefit in one adult study.10 Fluoxetine was helpful in treating depression in patients with fibromyalgia but did not improve pain symptoms. The agent has been shown to have analgesic properties in animal pain models.10
SSRIs are often prescribed for anxiety and depression and can be helpful if these comorbid symptoms arise in the context of an unremitting pain syndrome. Fluoxetine is the only SSRI for depression currently approved by the FDA for use in children. Fluoxetine and its active metabolite, norfluoxetine, have long half-lives and inhibit medications metabolized through the cytochrome P450 enzymes 2D6 and 3A/4. As a result, clinicians must be cautious in using this agent with other medications.
Psychiatrists often use citalopram or sertraline because they interact with fewer drugs. Drug interactions with medications that enhance serotonin release such as sumatriptan and tramadol may lead to toxic "serotonin syndrome," which is characterized by myoclonus, hyperreflexia, tremor, increased muscle tone, fever, sweating, shivering, diarrhea, delirium, and, rarely, coma.13
Abrupt cessation of most SSRIs, especially paroxetine (but not fluoxetine), often results in withdrawal effects, so taper off patients over at least a week. Withdrawal symptoms include dizziness, lethargy, parethesias, nausea, vivid dreams, irritability, and depressed mood. TCAs and SSRIs also can be associated with an increase in dental caries because of dry mouth. Advise patients to practice good dental hygiene and let their dentists know they are taking these medications.
Atypical antidepressants include venlafaxine, bupropion, mirtazepine, and nefazodone. Venlafaxine is a promising treatment for pain because it is a 5HT and NE inhibitor and may block those pain receptors.10 It is a potent inhibitor of serotonin and norepinephrine reuptake and a weak inhibitor of dopamine reuptake. It has fewer anticholinergic properties than TCAs and SSRIs, which may increase adherence in the treatment of neuropathic pain. Venlafaxine is not FDA-approved for children; controlled trials of venlafaxine in adults for pain management are under way.
Venlafaxine's adverse effect profile is similar to that of SSRIs. Blood pressure must be monitored regularly, however, because of potential idiosyncratic hypertensive reactions. No correlations have been established between specific venlafaxine blood levels and clinical responses.
A variety of anticonvulsants are used to manage pain. Physicians prescribe anticonvulsants less often for children than for adults because they require fairly frequent hematologic, hepatic, and blood level monitoring. Carbamazepine is approved for treatment of seizures and bipolar disorder. It is the only FDA-approved drug for trigeminal neuralgia. Carbamazepine is thought to suppress abnormal neuronal discharges at sites of nerve injury via sodium channel blockade.14 Drug levels, liver function tests, and CBC need to be monitored often. Drug interactions (lowering of other medication blood levels through hepatic induction) are common and should be evaluated regularly when using this medication.
Neurologists use valproic acid for migraine prophylaxis. While the mechanism of action is unknown, the agent is thought to increase gamma-aminobutyric acid (GABA) neurotransmission and brain concentrations of GABA, reducing spontaneous neuronal firing and decreasing neuropathic pain.14 Some small studies suggest that valproic acid is helpful and well tolerated. Although infants in the first two months of life have a markedly decreased ability to eliminate the drug, children between 3 months and 10 years of age have 50% higher clearance per weight than adults.4 Given the potential toxicity and highly variable metabolism of valproic acid, blood levels should be monitored regularly.
Recently, the anticonvulsant gabapentin has become popular for managing pain. It is reported to have infrequent and benign side effects at high doses and to be effective in relieving neuropathic pain. In addition, it is not necessary to monitor blood levels. Gabapentin is often prescribed in chronic or neuropathic pain, diabetic neuropathy, postherpetic neuralgia, and migraine prophylaxis. A recent case report describes successful use of gabapentin for pain management in a newborn with amyoplasia congenita and resultant contractures and dislocated joints.15 In children younger than 1 year, oral clearance is highly variable. In children 3 to 4 years of age, 40 mg/kg/day was needed to achieve plasma concentrations equal to those in children 5 years and older taking 30 mg/kg/day.4 Dosages must be decreased in individuals with renal compromise or on hemodialysis.
No significant drug/drug interactions with gabapentin have been reported. Nonetheless, gabapentin generally should be tapered off over a week or longer to avoid withdrawal reactions.
Clonazepam is an anticonvulsant, anxiolytic, and antiemetic. It is considered a third-line agent in the treatment of neuropathic pain (TCAs and anticonvulsants are first- and second-line drugs, respectively). It has not been shown effective in blinded clinical trials, but anecdotal reports suggest it is helpful in trigeminal neuralgia and other atypical pain syndromes. Clonazepam also may be useful in managing the comorbid anxiety that may amplify pain symptoms. It is thought to act by potentiating inhibitory GABA transmission, but its analgesic effects may be more related to its antianxiety and antispasticity properties.14
Most child psychiatrists try to avoid excessive use of benzodiazepines because parents and physicians are concerned about children becoming dependent on them at an early age and uncertain about the long-term neurodevelopmental effects these medications may have. Children also may experience significant sedation and behavioral disinhibition effects. Drug interactions with other sedating medications should be evaluated regularly when using this medication.
Clonidine is an
-adrenergic blocker, generally used to manage hypertension, Tourette syndrome, attention deficit hyperactivity disorder, and aggressive behaviors. In pain management, it is used to mitigate opioid withdrawal. Clonidine acts similarly to endogenous norepinephrine and activates autoinhibitory presynaptic receptors in the locus ceruleus. It therefore decreases hyperarousal symptoms. It is also thought to indirectly alter the dopamine and serotonin systems.16 Clonidine is used in low dosages in newborns to decrease symptoms of opioid abstinence syndrome and with methadone in narcotic weaning protocols.
Drug interactions occur with central nervous system depressants and anticholinergic agents. TCAs may decrease the hypotensive effects of clonidine. Clonidine also decreases the effects of ß-blockers and should be tapered first if both are being used. Clonidine must be tapered gradually over a week or more to avoid rebound hypertension, especially in children with gastrointestinal illnesses with vomiting.4
Propranolol is a ß-adrenergic blocker used in a variety of conditions such as hypertension, angina, cardiac arrhythmias, myocardial infarction, essential tremor, hypertrophic subaortic stenosis, and pheochromocytoma. It is also used for migraine prophylaxis and has been tried, with mixed success, in phantom limb pain.17 The mechanism of therapeutic action in pain management is unknown, but ß-adrenergic receptors have been demonstrated on pial vessels of the brain. No therapeutic blood levels have been established, but pulse and blood pressure should be monitored regularly. Do not use ß-blockers in patients with asthma or cardiac conditions because they can provoke bronchospasm and worsen bradycardia. Interactions with a wide variety of drugs such as insulin, anticonvulsants, oral birth control, and narcotics are common and should be evaluated regularly. A recent review suggests that ß-blockers are not associated with increased depression, fatigue, or sexual dysfunction in adults.18 Nonetheless, clinicians should monitor mood symptoms when using ß-blockers, especially in children who have had a previous episode of depression or who have a family history of depression.
This drug is known most commonly as an antitussive agent. It is a low-affinity, noncompetitive n-methyl-d-aspartate (NMDA) antagonist and is the d-isomer of a codeine analog. Dextromethorphan is thought to block the ion channel associated with the NMDA receptor and also increases the amount of 5-HT at central synapses. For pain management, it has been tried in diabetic neuropathy, in phantom limb pain, and as an opiate adjuvant. At least two randomized controlled trials have shown that high doses of dextromethorphan (about 400 mg/day), provide better pain relief than placebo for adult patients with diabetic neuropathy but not for postherpetic neuralgia. Side effects include sedation, dizziness, and confusion.10 In pediatric populations, dextromethorphan also has been used as an opiate adjuvant in postoperative pain management, resulting in use of lower morphine dosages.1921
Many psychotropic medications are now being prescribed for pain management in children. Some agents show promise but need further investigation in children and adolescents. Pediatricians should be aware of these potentially useful new indications and regularly evaluate potential drug interactions in their young patients.
The author is grateful for the assistance of Dr. Steven M. Holland and Dr. Donald Rosenstein in editing this manuscript before submission.
1. Zito JM, Safer DJ, dosReis S, et al: Psychotropic practice patterns for youth: A 10-year perspective. Arch Pediatr Adolesc Med 2003;157:17
2. Food and Drug Administration, Personal Communication, October 2002
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21. Dawson GS, Seidman P, Ramadan HH: Improved postoperative pain control in pediatric adenotonsillectomy with dextromethorphan. Laryngoscope 2001; 111:1223
The following case histories offer some examples of how various types of psychotropic medications have been used successfully to manage pain in children.
Tricyclic antidepressant for headaches
Harry, a 12-year-old, has had chronic headaches since he was 6 years of age. Initially, ibuprofen was intermittently helpful, but then Harry began to miss a significant amount of school because of his headaches. At 9 years of age, he developed weekly migraines with eye pain and vomiting. Neurologic and allergy evaluations concurred that he had migraines. Harry was treated with a variety of nonsteroidal anti-inflammatory drugs, sumatriptan, acupuncture, biofeedback, and a lactose-free diet. The headaches finally improved with low-dose amitriptyline, but it was discontinued after a month. Harry's school attendance did not improve, and his headaches returned. Harry's neurologist considered valproic acid for migraine prophylaxis. A child psychiatrist also saw Harry for his chronic pain and school absences. Low-dose nortriptyline was instituted for migraine prophylaxis and citalopram for anxiety and depressive symptoms. Harry's headaches decreased in severity and frequency, and he was able to attend school regularly within six months.
-adrenergic blocker for chronic abdominal pain
Sally, a 13-year-old, has chronic abdominal pain and intermittent vomiting of unknown cause, which was evaluated during a prolonged hospitalization. She has taken various opioids, such as morphine, hydromorphone, and a fentanyl patch to manage her pain, and the pain has gradually resolved. An anesthesiologist suggested a clonidine patch to facilitate her opioid taper, which she tolerated well.
Atypical antidepressant in a girl with neuropathic pain
Kay, 18 years old, was diagnosed with cerebral palsy at birth. She was referred for treatment of neuropathic pain in her feet, which has progressed since corrective surgery was performed for bilateral heel-cord lengthening. Initially, a pediatric anesthesiologist treated her pain with nortriptyline, a transcutaneous electrical nerve stimulator unit, and acupuncture. Gabapentin was associated with significant improvement in the neuropathic pain. A child psychiatrist treated Kay's comorbid depression with citalopram. Her mood improved, but the selective serotonin reuptake inhibitor (SSRI) caused increased muscle tone and worsening of muscle spasm pain, which triggered Kay's neuropathic pain. Venlafaxine was substituted for citalopram. Although it was not as effective as the SSRI for treating depression, it did not aggravate the neuropathic pain.
Dextromethorphan for sickle-cell-related pain
A 14-year-old boy, Paul, has sickle cell disease and daily headaches. He has had many hospital admissions for painful crises, aplastic crises, acute chest syndrome, priapism, and microinfarcts in the brain. He has received standing doses of slow-release oxycodone, oxycodone with acetaminophen, and morphine liquid for pain management, as well as treatment with folic acid, hydroxyurea, carbamazepine, and transfusions. His most recent headache pain was found to be caused by a neuroma, which was relieved immediately by steroid injection. Carbamazepine, which had been started for neuropathic pain, was discontinued. Paul had a history of contact dermatitis to clonidine patches. To assist with opioid taper, a pediatric anesthesiologist suggested a trial of dextromethorphan. During admission, Paul's opiate requirement decreased, and he tolerated the dextromethorphan well.
In June 2003, authorities in the United Kingdom, after examining unpublished data provided by the manufacturer of the selective serotonin reuptake inhibitor paroxetine (Paxil), recommended that the drug not be used in children and adolescents under 18 years of age. The Food and Drug Administration immediately followed up with a statement that it is reviewing reports of increased risk of suicidal thinking and suicide attempts in patients under 18 years treated with paroxetine for major depressive disorder. The FDA recommended that until its review is complete paroxetine not be used in children and adolescents under 18 years. However, pediatric patients already receiving treatment with paroxetine should not discontinue the medication abruptly and not without first talking to their doctor.
Recent reports about other medications such as sertraline and venlafaxine suggest that manufacturers are still in the process of determining the safety and efficacy of these medications for depression in children and adolescents. Parents should be made aware of this fact.
SSRIs have been on the market for more than 10 years and are much less likely than tricyclic antidepressants to result in fatal overdose. There appears to be little difference among SSRIs with respect to overdose safety. Lessons from fluoxetine, which is FDA-approved for treatment of depression and obsessive-compulsive disorder in 7- to 17-year-olds, suggest that the relationship of suicidal thinking and suicide attemptswhich may be an inherent risk in depressionto medication treatment is complex. No causal relationship between fluoxetine and risk for suicide has been established to date despite combined meta-analysis and controlled, prospective trials.
As with all medication use, the risk-benefit ratio must be assessed in each clinical situation and the child closely monitored for the desired outcomes, such as improved mood, decreased anxiety, or improved pain management.
2. Barbey JT, Roose SP: SSRI safety in overdose. J Clin Psychiatry 1998;59(suppl 15):42
Maryland Pao. Managing pain: An exploration of psychotropic medications. Contemporary Pediatrics October 2003;20:43.