Chronic Pain of Childhood: A Pharmacologic Approach

Symposium on Recurrent Pain in Children

Chronic Pain of Childhood: A Pharmacologic Approach Peter G. Lacouture, M.S., Pierre Gaudreault, M.D., and Frederick H. Lovejoy, Jr., M.D.

There are few areas in pediatrics more difficult and more frustrating to manage than chronic pain. While not a leading cause of mortality, pain is a cause of significant morbidity. Chronic pain is relentless and persistent, difficult to diagnose, and a continuous challenge for the pediatrician. If allowed to progress, physical and psychological effects often combine to disrupt a child's normal development. Because of these complexities, there are possibly no two physicians who approach the management of chronic pain the same way. This is because the diagnosis, pathophysiology, psychology, and treatment are all poorly understood. Unlike acute pain, an absolute cause is often difficult to firmly establish and the management requires careful individualization of therapy. Clinical research into pain of adolescents and children is not extensive, and most reports provide only opinion, often based on very little fact. Until further research is conducted on this problem, individualized therapy must be adjusted on a patient-to-patient and day-to-day basis. Every patient presents as a specific problem, and patients and physicians must understand from the outset that it will be necessary in most instances to explore a number of different modes of therapy. 3~Therefore, it is our intent to provide the reader with the pharmacologic tools useful in managing chronic pain in childhood. Chronic pain has a number of definitions, but at the same time it has none. Webster's Dictionary defines it as pain of long duration; continuing; constant. It is quite clear that chronic pain is easily labeled but not easily defined. Most common references for physical diagnosis deal extensively with pain, but do not address the issues of chronic pain in children. While an absolute definition of chronic pain appears difficult, six important char-

From the Department of Medicine and the Division of Pharmacology and Toxicology, The Children's Hospital, and Harvard Medical School, Boston, Massachusetts Dr. Gaudreault was supported by a grant from the Medical Research Council of Canada, Ottawa, Ontario, Canada

Pediatric Clinics of North America-Vol. 31, No. 5, October 1984

1133

1134

PETER G. LACOUTURE, PIERRE GAUDREAULT AND FREDERICK

H.

LOVEJOY

acteristics may help to better identifY chronic pain patients as those who have: 1. pain of greater than 6 months duration 2. multiple complaints with no apparent somatic link 3. been seen by many physicians 4. had multiple diagnostic tests 5. preoccupation with pain 6. behavior changes4 To better understand chronic pain one can make broad comparisons with acute pain (Table 1). It is useful to emphasize that "whereas acute pain may promote survival, chronic pain is usually destructive. " 28 Furthermore, while acute pain usually evolves from tissue disruption or damage, chronic pain evolves from a more diffuse origin-that is, cortical interpretation involving learned behavior, past experiences, and conditioned responses. Many types of chronic pain exist (Table 2). They can be divided into two major groups, requiring two different therapeutic approaches. The first is chronic pain with a well-defined organic cause, such as cancer; the second is chronic pain without a clearly identified organic basis, such as recurrent abdominal pain. Therapy for chronic pain with an organic etiology most often involves the use of analgesics; while therapy for chronic pain with no apparent organic basis may be multidimensional, involving analgesics plus psychotropics. In its most basic form, chronic pain consists of two strong components: one physical and one psychological. The physical component involves transmission of painful stimuli through specialized afferent nerve roots. The psychological component is more complex, involving interpretation of painful (physical and nonphysical) stimuli that manifest themselves as anxiety or depression. These components of chronic pain can be best viewed in a vect-o-graph (Fig. 1). The purpose of this vect-o-graph is twofold: first, it allows one to envision the major components responsible for chronic pain; and second, depending on vector strength, it allows one to develop a rational approach to therapy. Vectors nearest the somatogenic axis will respond to analgesics. Vectors nearest the depression axis require psychopharmacologic intervention. Vectors nearest the anxiety axis require anxiolytic agents. As children are therapeutic orphans for drug dosing, so too are they orphans with regard to therapy for chronic pain. Current thoughts and axioms for therapy of chronic pain have all been developed and tested in

Table 1.

The Differing Spectrums of Acute and Chronic Pain

ACUTE PAIN

CHRONIC PAIN

Self-limiting Warning system Anxiety Controlled by analgesics Easily graded

Self-perpetuating No apparent purpose Depression Seldom controlled by analgesics Involvement difficult to assess

CHRONIC PAIN OF CHILDHOOD: A PHARMACOLOGIC APPROACH

Table 2.

1135

Types of Chronic Pain

Cancer (tumors and metastasis) Arthritis and hemophilia (articulations) Headache Low back pain Phantom limb

Chest pain Myofacial Recurrent abdominal pain Collagen vascular disease Muscle spasm

adults. It is likely that chronic pain is not the same entity in adults as it is in children. While physical parameters may be similar, psychological aspects may be quite different. Peer pressure will differ between adults and children, while financial gain and familial pressures will be clearly different. Clearly children with chronic pain should not be treated as small adults. These and other differences in chronic pain between adolescents, ANALGESICS AND ADJUNCTS

r1ANAGEr1ENT:

VECTOP- A MANAGEf1EriT:

ANALGESIC AND ANX IOL YTJCS

~ ....

"' X

< u

r1ANAGEr1ENT:

z

w

"' 0

f-

:%

ANALGESICS AND TRICYCLIC ANTIDEPRESSANTS

§l

I

I

r1ANAGEr1ENT:

I I

TRICYCLIC ANTI DEPRESSANTS

y r1AtiAGErlEIH:

TRICYCLIC AIITIDEPRESSANTS AND ANXIOLYTICS

Figure l. Vect-o-graph adapted from Black and Chapman. 5 The solid lines depict the three major components of chronic pain, while the broken lines are hybridized vectors from two axes. In a pharmacologic approach, the strength of involvement of each of the three axes will determine a logical therapeutic course. Vector A is constructed as an example of a child evaluated with mild depression, moderate anxiety, and severe somatogenic pain. The resultant vector indicates a pharmacologic approach utilizing analgesics alone or in combination with diphenhydramine or another mild sedative.

1136

PETER G. LACOUTURE, PIERRE GAUDREAULT AND FREDERICK

H.

LOVEJOY

children, and even infants and toddlers must be recognized, defined, and addressed for therapy to achieve successful results. In diagnosing chronic pain, it is important to realize that there are some features that are similar to acute pain and some that are very different. In chronic pain (organic and nonorganic), the most outstanding difference involves perception of the pain-that is, it is essentially a centrally mediated event. However, inadequate therapy to deal with both physical and psychological components of pain leads to a worsening of symptoms, with feelings of desperation and hopelessness. 32 In children, optimal treatment becomes paramount in order to preserve the childs' developing perception of self-image and ego.

CLINICAL ASSESSMENT A clear assessment is important for many reasons to the patient, family, and medical team. It is critical to clearly address whether a symptom or cause is being treated. Treatment of the former is fraught with difficulty and a high likelihood of therapeutic failure. The PQRST mnemonic is useful in accurately describing pain: P, provocation-palliative factors; Q, quality; R, region; S, severity; T, temporal factors.l 0 Provocation/Palliative Factors. Factors such as physical manipulation that intensify or relieve pain provide important clues to diagnosis and therapy. For instance, chronic pain associated with movement of certain muscle groups may suggest inflammation, which may benefit from antiinflammatory medications. Similarly, spasm may benefit from skeletal muscle relaxants. Pain exacerbated by deep breathing may indicate pleural or thoracic wall involvement. Factors that decrease pain are useful in developing a pharmacologic approach to therapy by indicating a likely cause. For instance, while migraine headaches are frequently ameliorated by an erect position, headaches from brain neoplasms may be ameliorated by a reclining position. Quality. Quality of pain may be described in a number of ways, including sharp, burning, lancinating, dull, or aching. Sharp pain is the most difficult to deal with and usually requires potent analgesics. Burning pain is usually superficial and may respond to less potent analgesics or antiinflammatories. Lancinating pain, commonly described as electric-like shocks, has been most effectively managed with carbamazepine or phenytoin. Dull, throbbing or aching pain is the most common and is generally managed by multiple therapeutic agents, including the central and peripheral analgesics. Region. The site of pain, whether localized or diffuse, is important to identify. It may help to determine whether pain is originating from an underlying structure or is referred. Pain emanating from joints may be treated with antiinflammatory agents. Abdominal pain may be caused by smooth muscle spasm, a clinical situation in which the use of narcotics may be contraindicated. In settings in which smooth muscle tone is already elevated, meperidine may be the agent of choice. Severity. The severity and intensity of pain is important, though dif-

CHRONIC PAIN OF CHILDHOOD: A PHARMACOLOGIC APPROACH

1137

ficult, to establish. Accurate assessment of severity will often guide selection of therapeutic agents. Treatment of severe pain with mild analgesics is destined to fail, while potent analgesics may not be necessary in cases of mild pain. Description of the pain in comparison to other well known situations may aid in determining the severity of pain. This is done by asking the patient to describe and quantifY pain in terms of a toothache, a sprained ankle, a sunburn, or a muscle cramp. Temporal Factors. The time of day and the duration of pain should be carefully defined. In situations in which nighttime pain occurs, utilization of the "extended effects" of medication (sedation) may prove beneficial. Another examples involves headache symptomatology; that is, headache occurring late in the day could indicate a primary muscle tension headache. PHARMACOLOGY In this section we will not attempt to provide a protocol for the therapy of chronic pain but will rather provide the tools with which to fashion individualized treatment. Therapeutic agents used in the treatment of chronic pain include: (1) the analgesics, (2) the psychotropic agents, and (3) a miscellaneous group. The Analgesics The analgesic agents to be used in chronic pain can be divided into central- and peripheral-acting agents. The former group consists of the opiate and opioid compounds, while the latter group consists of the salicylates, acetaminophen, and the new nonsteroidal antiinflammatory drugs. Central Analgesics The opiate and opioid compounds are the most commonly used agents in pain relief. These compounds are generally absorbed quite well from the gastrointestinal tract (even though morphine is poorly absorbed), reach peak concentrations within 30 to 60 minutes, and are rapidly distributed throughout the body. Opiates are primarily metabolized in the liver. About 90 per cent of a single dose is glucuronidated, n-demethylated, or oxidized, in the first 24 hours. The duration of analgesic action coincides in general with the rate of metabolism (Table 3). Although there are differences among agents, hepatic metabolism is primarily responsible for termination of activity. Notable exceptions include codeine, which is metabolized to an active species (morphine), and meperidine, which is metabolized to a compound that is toxic to the central nervous system (normeperidine). Because of a relatively large "first pass" effect by the liver (or poor absorption), oral doses may be 2 to 6 times parenteral doses. As a specific example, the oral:parenteral dosage ratio for methadone is 2:1, meperidine 4:1, and morphine is 6:1. 23 In general, all of the members of this family produce tolerance and dependence and are associated with frequent and sometimes

1138

PETER G. LACOUTURE, PIERRE GAUDREAULT AND FREDERICK

Table 3.

H.

LOVEJOY

Duration of Action of the Central Analgesics

Very short acting ('12---2 hrs) Alphaprodine Fentanyl Short acting (2---3 hrs) Butorphanol Meperidine Pentazocine

Intermediate acting (3---8 hrs) Morphine H ydromorphone Levorphanol Nalbuphine Oxycodone Oxymorphone Methadone Long acting (16-24 hrs) Buprenorphine

severe side effects. They are generally potent analgesics effective against dull or aching pain. Mechanism of Action. The basis of action of these compounds still remains unclear despite the identification of endogenous "opiate-like" substances and multiple receptor sites. These sites of action in the central nervous system have been shown to include the spinal cord, the medullary, and pontine regions of the brain stem, and the hippocampus. In these areas they affect the release of various neurotransmitters; that is, they decrease acetylcholine release, 21 increase serotonergic31 and adrenergic activity,17 and antagonize dopaminergic effects. 26 It is generally agreed that the opiates do not affect the painful stimuli, but rather its perception and interpretation. These compounds make up a fairly homogeneous group of compounds, as listed in Table 4. Advantages and Disadvantages. The major advantage of this group of agents in chronic pain is their effectiveness as analgesics. While not effective against all types of pain, they are the most effective overall. Another advantage of these agents is variable potency ranges dependent on the agent selected. Additionally, their sedating properties can be beneficial. Their major disadvantage is the development of tolerance (needing higher doses) and their affinity for dependence. As their sedating effects may be advantageous, so may they be unwanted. Side Effects. The major effect of these agents on the central nervous system is analgesia, which is often accompanied by drowsiness and changes in mood. Sedation is a common finding that can be of therapeutic value for patients who need a good night's sleep along with pain relief. While euphoria is often seen, disphoria may result, especially in children. Additional central nervous system effects include pupillary constriction (miosis), respiratory depression, due to a reduced responsiveness of the brain stem respiratory center to increased pC02, and nausea and vomiting due to direct stimulation of the medullary chemoreceptor trigger zone (CTZ). In therapeutic doses, these compounds have little or no effects on heart rate or blood pressure. However, peripheral vasodilation resulting in orthostatic hypotension may be due to local vasodilator effects and central mechanisms as well as histamine release. Histamine release has also been associated with urticaria and skin rash (commonly associated with codeine analogs).

I

C1

i n

~

z 0

Table 4.

"1j

The Narcotic Analgesics

C1

=

DOSAGE AGENT

(ORAL)

INDICATION

SIDE EFFECTS

Morphine

.5mg/kg/q 6 hrs

Codeine

.5mg!kg/dose to 60 mg/dose q 4 hrs lmg!kg/dose to lOOmg/dose q 4 hrs

Mild to moderate pain Moderate to severe pain

.2mg/kg/dose to lOmg/dose q 6 hrs .05-.lSmg/kg/dose to 10 mg/dose q 4-5 hrs .05-.lmg/kg/dose to 5mg/dose q 6 hrs

Severe pain

See morphine

Moderate pain

See morphine

Moderate to severe pain

See morphine

Meperidine (Demerol) Methadone (Dolophine) Oxycodone Hydromorphone (Dilaudid)

Severe pain

CNS depression; orthostatic h}'potension; decreased G. I. motility; mental clouding Metabolic; see morphine See morphine

COMMENTS

Tolerance or dependence may develop

~

>

Converted to morphine; elevated level of ~ tolerance > Caution in renal failure; less sedation; may ~ trigger bronchial asthma; may lead to CNS > excitation Long half-life; minimal euphoria

8 b

Short half-life; excellent short-term effects; commonly combined with aspirin (Percodan or acetaminophen (percocet) Well absorbed; commonly used in terminal pain

C) ....

n

I :I:

..... ..... &5

1140

PETER G. LACOUTURE, PIERRE GAUDREAULT AND FREDERICK

H.

LOVEJOY

These opiate and opioid compounds produce a number of effects on the gastrointestinal tract. In the stomach, these agents may decrease secretion of hydrochloric acid and increase smooth muscle tone of the stomach, leading to an appreciable delay in gastric emptying. In the small intestine, there is also a decrease in secretions and an elevation in smooth muscle tone, leading to a decrease in peristaltic activity with subsequent constipation. Similar effects are seen in the large bowel, the biliary tract, and the urinary bladder. Effects of Disease States and Drug Interactions. These agents are metabolized by the liver (with some exceptions) and may potentially be affected by hepatic diseases. The required adjustment may be a reduction in dose (hepatic dysfunction may produce an increased sensitivity to narcotics) or more commonly an increase in dosing interval. 27 Half-lives may be doubled in patients with active liver disease. Furthermore, an increased percentage of an oral dose will reach the systemic circulation owing to a decreased first-pass effect. Renal disease may, in some cases, lead to accumulation of toxic metabolites (meperidine) or parent compound (morphine). Adjustments in this case may also require either a reduction in dose or, more likely, an increase in dosing interval. Respiratory depressant effects of the narcotics must be carefully considered in patients with decreased respiratory reserve, which can lead to acute increases in pC0 2 • 27 Drug interactions with the narcotic agents primarily involve additive central nervous system depression. Concurrent administration with ethanol leads to an additive (possibly supra-additive) effect, leading to increased drowsiness, lethargy, and decreased coordination. Similar effects are noted with sedative/hypnotics, minor tranquilizers, antihistamines, phenothiazines, and the tricyclic antidepressants. Severe reactions have been documented when meperidine is administered to patients receiving MAO inhibitors, thus their coadministration is contraindicated. Narcotic Drug Use. A discussion of analgesic therapy would not be complete without a few observations on the abuse of analgesic medications. Heavy criticism has been directed toward the medical community by lay observers, but more importantly by fellow colleagues concerning the excessive use of medication. The majority of this criticism concerns the narcotic analgesics, and it often is the result of misconceptions concerning addiction and habituation (dependence). While it is reasonable to assume that a given number of patients will develop a dependence upon a drug's effect, few, if any, become addicted. Addiction has been defined as a "behavioral pattern of compulsive drug use, characterized by overwhelming involvement with the use of a drug, the securing of its supply, and a high tendency to relapse after withdrawal. " 19 Chronic pain patients may be dependent; they are not addicted. To help with these concerns, always approach analgesic therapy with care; that is, try nonnarcotic agents first. Second, use a longer-acting agent, which may be devoid of mood-elevating tendencies (such as methadone). Third, manage these patients on a set schedule, not "prn" schedules that may promote pain behavior (see the preceding article on psychological approach). Fourth, the patient's environment is critical. If a patient returns to an environment that is fertile for learned pain behavior, then

1

1 I

CHRONIC PAIN OF CHILDHOOD: A PHARMACOLOGIC APPROACH

1141

the likelihood for dependency on analgesics is high. Last, and most important, suspected problems or potential problems in this area should be referred to multidisciplinary pain clinics. If this is not feasible, their advice should be sought freely. This approach does not support the wholesale use of narcotic analgesics, but rather a careful, thorough consideration of all factors involved. Peripheral Analgesics

The second major grouping of analgesic agents is the peripherally acting agents. While these agents may also exhibit central activity (aspirin and acetaminophen), their analgesic effects are primarily peripheral (aspirin, acetaminophen, and nonsteroidal antiinflammatory drugs). Unlike the centrally acting analgesics, this group is not nearly so structurally homogeneous (Table 5). These compounds represent two of the most commonly used over-thecounter analgesics, aspirin and acetaminophen. These agents are well absorbed from the gastrointestinal tract, within 30 minutes, and are distributed throughout the body water. Like the opiates, both aspirin and acetaminophen depend largely on hepatic metabolic activity for termination of activity. With acetaminophen, it is the parent compound that is largely responsible for its therapeutic effect, whereas, with aspirin, extrahepatic hydrolysis (primarily in the gastrointestinal tract and blood) leads to the active moiety, salicyclic acid. Unlike the opiates, aspirin absorption occurs to a great extent from the stomach, thereby avoiding a "first pass" effect of the liver. Although in high doses they may be effective against moderate pain, their predominant use is for mild pain. Pain associated with inflammatory conditions benefits most from salicylate and nonsteroidal antiinflammatory therapy. They are available for oral use only. While they do not demonstrate tolerance or dependence, they may be associated with serious side effects, especially in long-term therapy. Aspirin has proven effective as an analgesic, an antipyretic, and an antiinflammatory. The nonsteroidal antiinflammatory drugs, while acting in a manner very similar to that of aspirin, have not been used extensively as antipyretics. The nonsteroidal anti-inflammatory drugs are also well absorbed, although not as rapidly as aspirin and acetaminophen. They, too, are metabolized by the liver, but their half-life is significantly longer. Mechanism of Action. The basis of action of these compounds may be complex and is certainly not well understood. However, most sources indicate that aspirin and the nonsteroidal antiinflammatory drugs act by directly inhibiting the cyclo-oxygenase system responsible for the generation of prostaglandin compounds, which in turn may be intimately linked to antiinflammatory and possibly analgesic and antipyretic effects.2° From this proposed mechanism, the most effective use of these agents would be in settings in which inflammatory reactions play a major role in the generation of painful stimuli. These drugs also demonstrate analgesic properties separate from noninflammatory actions. The difference between aspirin and the nonsteroidal antiinflammatory drugs is the "irreversible" acetylation of the cyclo-oxygenase system by aspirin as opposed to the "reversible" effects of the nonsteroidal antiinflammatory drugs. Acetaminophen's

l

,.... ,.... ..... t-0 Table 5.

"'tt trl >-l

The Nonnarcotic Analgesics

trl

::0

DOSAGE AGENT

Salicylates Aspirin (multiple)

Diflunisal * Acetaminophen (multiple)

Nonsteroidal Antiinflammatories Tolmetin

Motrin* Naprosyn* Clinoril* Indoprofen*

(ORAL)

INDICATION

SIDE EFFECTS

COMMENTS

0

1G-15mg/kg/to 1 g/dose q 4--6 hrs

Mild pain especially with inflammatory processes

Bleeding, hypersensitive, GI distress

Risk of toxicity (metabolism saturation), may enhance effects of oral hypoglycemics; prolonged action. Good therapeutic index

0

500mg q 12 hrs 1G-20mg/kg/to 1 g/dose q 4--6 hrs

200-400mg q 6 hrs

40G-800ll)g q 6 hrs 25G-500mg q 8--12 hrs 200mg q 12 hrs 5G-200mg q 6 hrs

See Aspirin Mild Pain

Fewer bleeding abnormalities, G. I. upset (low incidence)

~ ~ ::0

.trl

"'tt

[;;

5ltrl 0

6 tl Mild Pain, for chronic joint disease See Tolmetin

Hypersensitivity; dyspepsia; abdominal discomfort; renal insufficiency; cholestatic hepatitis See Tolmetin

Expensive; well absorbed

~

6 t"'

>-l

~

See Tolmetin

See Tolmetin

tl "-'1

See Tolmetin

See Tolmetin

trl

See Tolmetin

See Tolmetin

*Use of these drugs in children has not yet been approved.

~

tl

::0 c=J :>;

::r:

r ~

..!:1 0

~

CHRONIC PAIN OF CHILDHOOD: A PHARMACOLOGIC APPROACH

1143

clinical effects may in part be related to similar mechanisms, but its major action is unknown. It has also further been demonstrated that acetaminophen may also produce a significant effect on pain pathways mediated by the central nervous system. Advantages and Disadvantages. The major advantage of these agents is that they are readily available and relatively safe. Aspirin and acetaminophen are available without prescription and are inexpensive, while the nonsteroidal antiinflammatory drugs are available by prescription only and are relatively expensive. Because their action is primarily peripheral in nature, they do not produce central nervous system manifestations: somnolence, mood changes, euphoria, and so on. In chronic pain, these agents lend themselves to combination therapy with virtually any agent. The major advantage of these compounds is that they do not produce tolerance or habituation. Disadvantages associated with these agents primarily involve the nonsteroidal antiinflammatory drugs and aspirin. However, one common disadvantage to all these agents is that they are relatively mild analgesics. Side Effects. Side effects associated with acetaminophen are few, but those associated with aspirin and the nonsteroidal antinflammatory drugs may be significant. Aspirin's side effects include gatrointestinal hypersensitivity irritation, leading to ulceration; and hematologic effects, resulting in delayed clotting time. The gastrointestinal effects can be reduced in sensitive individuals by using buffered or enteric-coated preparations. While the nonsteroidal antiinflammatory drugs show fewer effects on blood coagulation, gastrointestinal irritation and hypersensitivity do exist. Furthermore, a number of the nonsteroidal antiinflammatory drugs have produced impaired renal function with chronic therapy (see Table 6). Effects of Disease States and Drug Interactions. All these agents are primarily metabolized by the liver, therefore hepatic disease may delay their clearance and require an increase in dosing interval. Additionally, aspirin should not be used in young children suffering from viral illness. Drug interactions include ethanol, which has been reported to increase gastrointestinal bleeding associated with the salicylates. Aspirin may also increase the effect of the oral hypoglycemic agents and may have its effect reduced by the corticosteroids. Acetaminophen may enhance the hypoprothrombinemic effects of warfarin. The nonsteroidal antiinflammatories may have their half-life reduced by concurrent administration with phenobarbital.

The Psychotropics The psychotherapeutic agents have long been important in the therapy of chronic pain in adults. While patients may benefit from these agents, their widespread use is generally to be avoided. This group of drugs is utilized primarily to manage the psychological effects of chronic pain (that is, depression). They may also potentiate analgesic activity (especially of narcotics) and produce a sedating or darning effect. This group

1144

PETER G. LACOUTURE, PIERRE GAUDREAULT AND FREDERICK

H.

LOVEJOY

of agents includes the tricyclic antidepressants, the phenothiazines, and the benzodiazepines (Table 6). Mechanism of Action. The analgesic action of these agents is completely central, interfering with biogenic amine systems in the central nervous system. Most of these agents also demonstrate a myriad of peripheral autonomic nervous system actions. The benzodiazepines have no direct effect on analgesic responses but produce central nervous system sedation. The phenothiazine and tricyclic antidepressant agents have a more well-defined role. The first and most commonly accepted role of these compounds is with psychiatric disturbances, but the second is that of true analgesic potentiation. Both the tricyclic antidepressants and the phenothiazines exert effects on central nervous system biogenic amines (primarily serotonin and dopamine), which are strong modifiers of pain. The demethylated tricyclic antidepressants, nortryptyline and desipramine, do not block serotonin uptake and are thus poor analgesics; but the methylated tricyclic antidepressants, amitriptyline, doxepin, and imipramine, do block serotonin uptake and have good analgesic activity. Similarly, the phenothiazines, perphenazine and fluphenazine, inhibit serotonin uptake and further block dopamine receptors, making them effective analgesics in chronic pain. 7• 18• 24 Advantages and Disadvantages. The major advantage to these compounds is that they can effectively manage and control underlying psychological changes that may have produced the pain or may have been a result of the pain. Furthermore, as with the narcotics, side effects produced by these drugs may prove to be beneficial (for example, nighttime sedation). The major disadvantages of these compounds are that they are toxic, relatively potent, exhibit many adverse reactions, and are associated with therapeutic failures. In adult populations, these agents may be more widely accepted than in pediatrics. In most cases, the disadvantages of these drugs outweigh their advantages. This does not mean that patients may not benefit from these agents. It does mean, however, that careful consideration must be taken before prescribing their use. Side Effects. Side effects from these drugs are many and can simply be viewed as centrally mediated events or peripherally mediated events (see Table 6). The centrally mediated side effects include headache, lassitude, and motor slowing. Most of these effects are dose related, and in many cases those responses will diminish with time. The peripherally mediated effects are those of the autonomic nervous system and more specifically the parasympathetic branch. Side effects are primarily anticholinergic, producing dry mouth, constipation, blurred vision, and tachycardia. These symptoms also are dose related. Tolerance or diminishing of these effects may not occur. Instead, patients learn to "tolerate" or "ignore" their effects. Effects of Disease States and Drug Interactions. There are few disease states that can alter these therapeutic effects; however heart disease, hepatic impairment, and seizure disorders may indicate care in their usage. The major drug interactions of the tricyclic antidepressants involve additive effects with central nervous system depressants such as ethanol, the antihistamines, benzodiazepines, and other sedative/hypnotics. As with

I

C1

i Ci

~

Table 6.

z

Psychotropics

----------------------------------------------------------------------------------------------~ SIDE EFFECTS COMMENTS AGENT DOSAGE INDICATION C1 =============================================================================== Tricyclic Antidepressants Amitriptyline (Elavil) Imipramine (Tofranil) Phenothiazines Perphenazine (Trilafon) Fluphenazine (Prolixin) Benzodiazepines Diazepam (Valium) Clonazepam (Clonopin)

t"' t:)

6yrs: IOmg 6-lOyrs: 10-20mg ll-15yrs: 20-50mg l-2mglkg/dose q 6 hrs ir ghs

Trigeminal neuralgia; depression Same as above

Dry mouth, tachycardia, lethargy, constipation, urinary retention, dilated pupils Same as above

.1 to .2mglkg/dose to 8mg/dose q8hrs · .02-.0Smg/dose to lmg/dose q 8 hrs

Posthepatic neuralgia

Extrapyramidal symptoms

.05-. 03mglkg/dose to IOmg q 8 hrs O.Imglkg/dose to .5mg/dose q 8 hrs

Sedation

:I: 0 0

!=?

>

~

May also possess significant ~ antiemetic effects ~

g 0

C'l .....

Ci

Lancinating pain

Agitation; irritability; CNS depression See Diazepam

Short term use only

~

~ 0

Low incidence of side effects~ :I:

.... .... oj>..

Q1

1146

PETER G. LACOUTURE, PIERRE GAUDREAULT AND FREDERICK

H.

LOVEJOY

meperidine, severe reactions with these drugs and the MAO inhibitors have occurred. The phenothiazines and benzodiazepines exhibit similar interactions. In addition both the phenothiazines and the tricyclic antidepressants have enhanced the analgesic effects of the narcotic analgesics.

Miscellaneous Agents The third group to be considered in the pharmacologic approach to chronic pain includes selected anticonvulsants, antihistamines, steroids, and skeletal muscle relaxants (Table 7). This group of agents is the most heterogeneous and least clearly understood. In fact, their role in the management of chronic pain is limited and indicated for selected cases of chronic pain. Mechanism of Action. The anticonvulsants are a curiosity primarily because their possible role seems untenable. They have been extremely effective in conditions characterized by lancinating pain, often of myofacial origin. 29 The mechanism by which these anticonvulsants operate is not clear; however, most attribute their beneficial effects to depression of synaptic transmission. The mechanism of action of the antihistamines is based on its primary effect (blockade of peripheral histaminergic receptors) and a side effect (CNS depression resulting in sedation). The basis of action of the steroidal agents is simply that of reduction of pain through reduction of inflammatory processes. These agents, through local injection or infiltration, have produced beneficial effects with short-term use.l· 15 They are most commonly utilized for joint involvement. The skeletal muscle relaxants have also been used, in limited instances. Those who benefit most from these agents are patients with pain from skeletal muscle spasm. Advantages and Disadvantages. The major advantage of steroid therapy is that it often can be administered once a week or once a month. The major advantage to the skeletal muscle relaxants is their effectiveness on skeletal (not smooth) muscle spasm coupled with a central effect that can be adjusted to produce sedation if desired. The major advantage of the anticonvulsants is their effectiveness for lancinating pain. All of these agents have disadvantages, with steroids being of greatest concern. Steroids must be given by injection, and they may have serious systemic effects if given too often or in excessive doses. Side Effects. Because this miscellaneous category covers such a diverse group of agents, side effects are equally diverse. The major side effect of the anticonvulsants is central nervous system depression, resulting in ataxia, nystagmus, lethargy, and sometimes confusion. Long-term side effects are gingival hyperplasia with phenytoin, and water retention with carbamazepine. Similarly the major side effects with the antihistamines include drowsiness, dry mouth, and tachycardia. In children, agitation and hallucinations may occur. Steroids have side effects that are usually associated with long-term use: Cushing's syndrome, muscle wasting, spontaneous bone fractures, secondary adrenocortical insufficiency, posterior subcapsular cataracts, electrolyte disturbances, and a number of other gastrointestinal, neurologic, dermatologic, and metabolic changes. Side effects

1

Table 7. AGENT

Anticonvulsants Phenytoin (Dilantin) Carbamazepine (Tegretol) Antihistamines Diphenhydramine (Benadryl) Hydroxinazine (Atarax) Skeletal Muscle Relaxants Diazepam (Valium) Carisoprodol (Soma)* Methocarbamol (Robaxin)*

DOSAGE

INDICATION

""" """ ""'"

SIDE EFFECTS

COMMENTS

2.5-4mglkg to 200mg q 12 hrs 4-lOmglkgldose to lOOmgldose q 8 hrs

Myofacial pain

lmglkg to 50mg q 6 hrs or qhs .5mglkg to 25mg q 6 hrs

Sedation

CNS depression

Used for its sedative property

Sedation, potentiation of narcotics

CNS depression

Excellent synergistic action with narcotics

6mg/kgldose to 350mgl dose q 6 hrs 15mglkgldose to 750mgl dose q 6 hrs

Myofacial pain, phantom limb pain

(see Table 3) Muscle spasm Muscle spasm

*These drugs have not been approved for use in children.

-l.

Miscellaneous Agents

Ataxia; nystagmus; CNS depression CNS depression

Weakness, dizziness

Gingival hyperplasia Water retention; multiple hematopoietic reactions (aplastic anemia); cholestatic jaundice

1148

PETER G. LACOUTURE, PIERRE GAUDREAULT AND FREDERICK

H.

LOVEJOY

associated with the skeletal muscle relaxants are drowsiness, light-headedness, dizziness, blurred vision, headache, and irritability. Effects of Disease States and Drug Interactions. Carbamazepine has been indicated for a number of adverse effects and therefore its careful administration in patients with significant histories of cardiac, hepatic, or renal damage or adverse hematologic reactions to other drugs is recommended. Because phenytoin exhibits a prolonged half-life and extensive hepatic metabolism, patients with hepatic dysfunction may require reduced doses. Both the antihistamines and the skeletal muscle relaxants are metabolized by the liver; therefore, prolonged action of these agents may occur with hepatic disease. Concurrent administration of cimetidine with carbamazepine has produced elevated levels of the latter and should be carefully monitored. Phenytoin's effects may be increased by cimetidine, salicylate, and phenylbutazone and decreased by the barbiturates. Both the antihistamines and the skeletal muscle relaxants may show increased central nervous system depression when concurrently administered with the sedative/hypnotics, ethanol, the phenothiazines, or the tricyclic antidepressants.

THE PSYCHOLOGICAL APPROACH The psychological effects of chronic pain (of organic or nonorganic origin) may be devastating and are often more far reaching than the physical effects. Patterns of behavior may emerge that may drastically alter the course of an otherwise normal development. Feelings of distrust, fear, contempt, and loneliness may become serious, requiring long hours of careful management and attention. It is important for the physician to observe how family members respond to the pain; for instance, family reactions may reinforce and promote pain behavior, thus prolonging and worsening the child's response to his pain. 23 In those instances pain can be a conditioned response .12 Behavioral modification techniques have been developed to deal extensively with learned and conditioned responses and can help prevent the switching from doctor to doctor or medication to medication.13· 14 If these abnormal reactions can be identified and properly rectified, therapy may be more predictable and more likely successful. The multidisciplinary pain clinic is often best equipped to handle these complex situations.

THE MULTIDISCIPLINARY PAIN CLINIC The multidisciplinary pain clinic may assist a physician in the case of complex pain or may actually assume the primary care of these patients. The structure and organization of these units have been carefully thought out and described elsewhere. 4· 16· 22 While pediatric chronic pain clinics at present do not exist, most adult clinics have the resources to help resolve pediatric chronic pain syndromes. Every patient is not necessarily a candidate for these specialized clin-

CHRONIC PAIN OF CHILDHOOD: A PHARMACOLOGIC APPROACH

1149

ics. Their assistance might be useful for patients who fail routine management, have a complex social history, have an unsettled family situation, are facing multiple endogenous and exogenous pressures, or where etiology is undiagnosed. Pain clinics offer two major advantages: (I) the time to deal in depth with these patients and (2) a multidisciplinary staff with specialization and experience. OTHER TREATMENT MODALITIES An additional line of defense against pain of a chronic nature involves the use of nerve blocks, hypnosis, acupuncture, transcultaneous nerve stimulation (TCNS) and dietary changes.1 1 A recent study reports the use of intraspinal narcotics infused by implanted reservoir in the management of chronic pain. Not unexpectedly, they report good results with cancerrelated pain but poor results with a nonmalignant pain. 8 While certainly considered a more radical approach, nerve blocks, if done properly, can produce dramatic therapeutic results while also being of diagnostic value3 (Table 8). Transcutaneous nerve stimulation is a simple technique which has worked in the past, (especially with pain from nerve damage), 30 but its success rate is highly variable and there is no way to predict its effectiveness. The method involves the surface placement of battery-powered electrodes that send electrical pulses (frequency and amplitude regulated) across the skin. It is a relatively benign mode of therapy with mild skin sensitivity as a possible side effect. The most radical approach to chronic pain involves peripheral neurectomy, cordotomy, rhizotomy, and other surgical procedures that should be limited to patients with severe localized pain and likelihood of short survival. 3 GENERAL CONSIDERATIONS The basic tools with which to effectively approach chronic pain of childhood have been provided. In order to properly handle these often difficult patients, one must understand a few general concepts.6, 25,33 1. Chronic pain is unique and challenging. If you don't have the time or the patience to deal with these issues, refer you patient to someone who does. Table 8.

Methods of Nerve Block

METHOD

INDICATION

Local Infiltration Sympathetic Block Cervicothoracic Prevertebral Splantic Nerves Somatic Nerve Cranial Nerves Spinal Nerves

Myofacial and some musculoskeletal pain Differential of head, neck and chest pain Low back pain Abdominal pain Differential in head and face pain Neck, shoulder, and chest pain

1150

PETER G. LACOUTURE, PIERRE GAUDREAULT AND FREDERICK

H.

LOVEJOY

2. Treat environmental problems first, then resort to medication for analgesic and behavior support, then more radical approaches (surgical intervention). 3. Try as much as possible to remove all medication during initiation of therapy. In the beginning, too many medications may cloud the picture. 4. Pain is never the same from patient to patient-don't expect the therapy that was effective on your last patient to be effective now. 5. When possible, treat causes first and symptoms second. 6. Chronic pain should be treated on a "time contingent" not "pain contingent" schedule, thereby eliminating pain as a learned behavior to obtain medication. This approach often leads to a reduction in habituation. 2 · 12 7. Drug action duration should be as long as possible to limit the number of doses ingested per day. 8. Drug regimen should be individualized and sufficient to achieve maximum relief with minimum side effects. 9. Judicious use of medication may also benefit from secondary or side effects, such as sedation in an anxious sleep-deprived child. 10. Adjunct drugs to control coexisting depression (tricyclic antidepressants) or anxiety (benzodiazepine) syndromes may be useful. 11. Period reassessment of the pain and treatment is essential. In selecting a pharmacologic approach, try as best you can to initially manage your patient with a single drug: it is best to handle one drug regimen at a time. Depending on the severity of the pain, a logical starting point is the peripheral-acting analgesics. If this is ineffective, combination therapy with mild central-acting analgesics may be considered. Most important, it cannot be stressed enough to give the patient initially what he or she needs. Children and adolescents in general will very rapidly develop distrust, anger, and discontent with undertreatment. Addiction is not an

issue! Finally, it is important to set goals and to strive to progress with therapy no matter how small the steps. This is psychologically uplifting for both patient and provider.

ACKNOWLEDGMENT

The authors are greatly indebted to Diane M. Bourgeois for the long, difficult hours spent with the word processor in preparing this manuscript.

REFERENCES 1. Barry, P. J. C., and Kendal, P. H.: Corticosteroid infiltation of the extradural space. Ann. Phys. Med., 6:267-273, 1962. 2. Bergman, J. J., and Werblun, M. N.: Chronic pain: A review for the family physician. J. Family Pract., 7:685-693, 1978. 3. Black, R. G., and Chapman, C. R.: The management of pain with nerve blocks. Minn. Med., 57:189--194, 1974. 4. Black, R. G., and Chapman, C. R.: The chronic pain syndrome. Surg. Clin. North Am., 55:999--1011, 1975.

CHRONIC PAIN OF CHILDHOOD: A PHARMACOLOGIC APPROACH

ll51

5. Black, R. G., and Chapman, C. R.: The chronic pain syndrome. Clin. Med., 82(5):17-20, 1975. 6. Budd, K.: Analgesic drugs. Pharmacol. Ther., 12:575--587, 1981. 7. Clarke, I. M. C.: The use of psychotropic drugs in the treatment of pain. Pharm. Med., 1:106, 1979. 8. Coombs, D. W., Saunders, R. L., Gaylor, M. S., et al.: Relief of continuous chronic pain by intraspinal narcotics infusion via an implanted reservoir. }.A.M.A., 250:2336--2339, 1983. 9. Cooper, S. A.: New peripherally-acting oral analgesics. Ann. Rev. Pharmacol. Toxicol., 23:617-647, 1983. 10. DeGowin, E. L., and DeGowin, R. L.: Bedside Diagnostic Examination. New York, Macmillan, 1976. II. Fields, H. L.: Pain II: New approaches to management. Ann. Neurol., 9:101-106, 1981. 12. Fordyce, W. E.: The office management of chronic pain. Minn. Med., 57:185-108, 1974. 13. Fordyce, W. E.: An operant conditioning method for managing chronic pain. Postgrad. Med., 53:123--128, 1973. 14. Fordyce, W., Fowler, R., and DeLateur: An application of behavior modification technique to a problem of chronic pain. Behav. Res. Ther., 6:105, 1968. 15. Forrest, J. B.: The response to epidural steroid injections in chronic dorsal root pain. Can. Anaesth. Soc. J., 27:40--46, 1980. 16. Gorsky, B. H.: Chronic pain: A management plan based on experience in a pain clinic. Postgrad. Med., 66:147-154, 1979. 17. Gunne, L. M.: Catecholamines and 5-hydroxytryptamine in morphine tolerance and withdrawal. Acta. Physiol. Scand. (Suppl.), 58:1-91, 1963. 18. Hendler, N.: The anatomy and psychopharmacology of chronic pain. J. Clin. Psychiatry, 43:15-20, 1982. 19. Jaffe, J. H.: Drug addiction and drug abuse. In Goodman, L. S., and Gilman, A. (eds.) The Pharmacologic Basis of Therapeutics. 5th ed. New York, Macmillan, 1975, pp. 245-283. 20. Kantor, T. A.: Control of pain by non-steroidal antHnflammatory drugs. Med. Clin. North Am., 66:1053-1059, 1982. 21. Kosterlitz, H. W., and Taylor, D. W.: The effect of morphine on vagal inhibition of the heart. Br. J. Pharmacol., 14:209-214, 1959. 22. Mehta, M.: The pain relief clinic. Pharmacol. Ther., 12:373-380, 1981. 23. Newburger, P. E., and Sallan, S. E.: Chronic pain: Principles of management. J. Pediatr., 98:180-189, 1981. 24. Obel, A. 0. K.: Management of chronic pain: Practical therapeutics. East Afr. Med. J., 59:429-432, 1982. 25. Ponte, C. D.: Pain and its pharmacologic manipulation. W. Virg. Med. J., 79:69-74, 1983. 26. Puri, S. K., Reddy, C., and Lal, H.: Blockade of central dopaminergic receptors of morphine: Effect of haloperidol apomorphine or benzotropine. Res. Commun. Chern. Pathol. Pharmacol., 5:389-430, 1973. 27. Rusy, B. F.: Individualization of narcotic analgesic therapy. Med. Clin. North Am., 58:ll37-ll4l, 1974. 28. Sternbach, R. A.: Chronic pain as a disease entity. Triangle, 20:27-31, 1981. 29. Swerdlow, M., and Candell, J. G.: Anticonvulsant drugs used in the treatment oflancinating pain: A comparison. Anaesthesiology, 36:ll29-ll32, 1981. 30. Thorsteinsson, G., Stennington, H. H., Stillwell, G. K., et al.: Transcutaneous electrical stimulation: A double blind trial of its efficacy for pain. Arch. Phys. Med. Rehabil., 58:8-13, 1977. 31. Way, E. L., Loh, H. H., and Shen, F.: Morphine tolerance, physical dependence and synthesis of brain 5-hydroxy tryptamine. Science, 162:1290-1292, 1968. 32. Weddington, W. W.: Longitudinal management of chronic pain. Comp. Ther., 9:14-20, 1983. 33. Wyant, G. M.: Chronic pain: Principles and treatment. Drugs, 267:262-7, 1983. The Children's Hospital 300 Longwood Avenue Boston, Massachusetts 02ll5