Pain management

C l i n i c a l R e v i e w A r t i c l e
Pain Management: Important Principles in
the Drug Management of Pain
Robert B. Supernaw, PharmD, DAAPM, DABFE
s in the management of almost any medical therapy. It is vital that such a goal be established from condition, the best pharmacotherapeutic ap- the start so that the patient is not disappointed with the proach in the management of acute and chron- reduction in the average pain level, when the results of Aic pain is no drug therapy at all. However, the pharmacotherapy leave the pain at any level above0.
option of not using drugs in managing many pain syn- Contemporary pain management not only focuses dromes is not realistic. When a clinician has determined on the mitigation of the pain but also includes the that the pain condition is substantial enough to affect the improvement of the patient’s quality of life. Although patient’s quality of life and that it cannot be treated solely pain intensity can largely be measured by using pain with physical medicine (eg, ice packs, massage, physical scales, the measurement of the quality of life of the therapy), drug therapy is indicated. When drug therapy patient with chronic pain includes an ongoing assess- is contemplated, there are several important principles to ment of the patient’s ability to perform self-care; the keep in mind. This article reviews important principles in patient’s ability to lift, walk, sit, stand, travel; the patient’s sleeping pattern; and the impact of the pain-producing condition and its treatment on the patient’s MEASURE PAIN REGULARLY
social and sex life. Adverse effects of drugs must also be As is the case for patients with high cholesterol taken into account. Often, while the pain is mitigated, levels, diabetes mellitus, or hypertension, the severity the concomitant effects of the drugs can adversely of the condition of the patient with chronic pain must affect the patient’s activities of daily living.
be assessed regularly. However, without an objectivemeasure of pain, it is difficult to determine the intensi- DIFFERENTIATE BETWEEN NOCICEPTIVE AND
ty of pain and measure the effectiveness and the effica- NEUROPATHIC PAIN
cy of any analgesic intervention. The simplest form of In addition to the intensity of pain, the nature of measurement—the one that is most easy for the pa- pain must be determined in order to select the best tient to understand and use appropriately—is the ver- pharmacotherapeutic approach. Whether the pain is bal analogue scale. With this system of pain measure- acute or chronic must be considered, as well as ment, the clinician asks the patient to grade his or her whether the pain is malignant, benign, organic, psy- pain intensity numerically from 0 to 10, with 0 equiva- chogenic, vascular, or depression related. lent to “no pain at all” and 10 representative of “pain as A common oversight in evaluating pain is not dif- bad as it can possibly be.” Although a verbal analogue ferentiating nociceptive pain from neuropathic pain.
scale, Likert scale, or visual analogue scale cannot mea- Neuropathic pain is addressed in a completely differ- sure pain in absolute terms, these scales provide the ent manner than is nociceptive pain. Simply stated, clinician with a relative assessment of the patient’s con- nociceptive pain is caused by activation of nociceptors by noxious stimuli (eg, trauma, intense heat or cold, Pain should be graded as mild, moderate, severe, or chemicals, tissue damage). The stimuli activate an excruciating before the drug regimen and drug deliv- intact nervous system pathway running from the point ery system are established. Also before treatment is of insult, through A-delta and C nerve fibers, to the started, it is important to ask what the patient’s goal of central nervous system. Nociceptive pain is usually treatment is. Before treatment is started, most patients described in such terms as stabbing, sharp, pinching, with chronic pain will state that a substantial reductionin their level of pain will be satisfactory. For example, apatient with an average pain level of 6 will most likely be Dr. Supernaw is the Associate Dean for Curriculum, Outcomes, and Students thrilled to achieve an average level of 2 or 3 with drug at Texas Tech University School of Pharmacy, Amarillo, TX.
Hospital Physician August 2002 45
S u p e r n a w : P a i n M a n a g e m e n t : p p . 4 5 – 5 2 or piercing. Such pain is generally responsive to the antiseizure medications usually requires doses that ex- more traditional analgesic drugs, including aspirin and ceed those necessary for seizure control.) other nonsteroidal anti-inflammatory drugs (NSAIDs), Although most texts have considered tricyclic antide- pressant agents as the mainstay in pharmacotherapy for Neuropathic pain occurs secondary to a damaged opioid-insensitive pain, the newer serotonin and nor- nervous system pathway, such as a severed, pinched, or epinephrine reuptake inhibitors, of which venlafaxine compressed nerNerve destruction is common in (Effexor) is the primary example, deserve considera- accident-related trauma, tumor-related disease, post- tion. Venlafaxine can be routinely administered in herpetic neuralgia, diabetic neuropathy, and trigemi- dosages of 75 mg to 300 mg daily and has been shown nal neuralgia. The pain is usually described as dull, burning, or electric-like. With nerve damage–related This category of antidepressant drug appears to dimin- chronic pain that is opioid insensitive, unconventional ish neuropathic pain and combats any associated de- drug therapy is indicated. Neuropathic pain is more pression, while causing a minimum of adverse effects.
likely to be responsive to antidepressant and anti- The more conventional tricyclic antidepressant drugs seizure medications and less likely to be responsive to (eg, amitriptyline [Elavil]), although well established as the more traditional analgesic medications.
effective in neuropathic pain control, are not well toler- Patients who provide the greatest clinical challenge ated by many patients. Adverse effects associated with have both opioid-sensitive (eg, nociceptive) and opioid- the tricyclic group of drugs include those related to the insensitive (eg, neuropathic) pain at different sites. Trials anticholinergic and sedative effects of this drug class. Of with traditional analgesic agents along with antidepres- particular concern are the adverse effects of blurred sant or anticonvulsant medications, such as carbamaz- vision, urinary retention, daytime drowsiness, and epine (Tegretol) and gabapentin (Neurontin), have weight gain. The visual and urinary problems are leg- been shown to be effective in mixed-pain syndromes.
end. (Hence the phrase, “can’t see and can’t pee.”) Be-cause of the adverse effects of the tricyclic agents, the CONSIDER THE NEWER MEDICATIONS FOR
newer antidepressant drugs may receive significantly NEUROPATHIC PAIN
greater attention in pain care in the future.
Antidepressant Medications
Most texts have considered tricyclic antidepressant Antiseizure Medications
drugs as the mainstay in pharmacotherapy for opioid- Carbamazepine has been the mainstay of antiseizure insensitive pain, including neuropathic pain. Antide- medication–related approaches to addressing neuro- pressant drugs are rather unique analgesic agents.
pathic pain; however, more recently, gabapentin has Clearly, antidepressant medications are effective in the also been beneficial in treating painful conditions not treatment of endogenous depression; considering that responsive to narcotic drugs. Carbamazepine is first one of the symptoms of depression is chronic pain— administered in the dosage of 200 mg 3 times daily; usually vague in description—antidepressant agents afterward, the dosage is increased to as much as 800 mg exert an analgesic effect indirectly by combating the daily. It is very effective in treating trigeminal neuralgia depressive illness. Antidepressant drugs also have an at higher dosages (ie, greater than 800 mg daily).
intrinsic analgesic activity that assists in chronic pain Gabapentin is similarly effective when administered in management. Additionally, these drugs may have a doses of 300 to 500 mg, with reports of efficacy at 900 to potentiating effect on narcotic medications, thereby 3600 mg (or higher) daily, in divided dosesPatients facilitating the management of nociceptive chronic who respond generally describe diminished levels of pain as well as neuropathic pain. The analgesic activity of antidepressant drugs is most likely a combination of Lamotrigine (Lamictal), in dosages of 50 to 400 mg daily, has been shown to be effective in treating tri- Studies have demonstrated the effectiveness of anti- geminal neuralgia, HIV-induced neuropathy, and post- depressant drugs in the management of chronic pain stroke neuropathies unresponsive to other pharma- in hundreds of patientsThe analgesic activity of anti- cotherapy. However, adverse effects have caused a depressant drugs occurs within 5 to 7 days, as opposed significant percentage of patients to withdraw from to the 10 to 14 days required for their antidepressant effects. Usually, analgesic effects are achieved at slightly Phenytoin (Dilantin) and valproic acid (Depakene) lower-than-normal doses than are required for anti- have also been used in treating neuropathic pain. How- depressant effects. (In contrast, pain mitigation with ever, they have not been shown to be uniformly useful 46 Hospital Physician August 2002
S u p e r n a w : P a i n M a n a g e m e n t : p p . 4 5 – 5 2 in several trials; data have yielded mixed results. There- gesic agents; however, in OTC doses (ie, doses below fore, these two drugs should be reserved for treatment the low doses of prescription NSAIDs), these agents failures with other antiseizure medications. exhibit little or no anti-inflammatory action. Onlywhen patients double-up on their doses (eg, achieving DO NOT DISCOUNT THE VALUE OF NONPRESCRIPTION
doses equaling the lowest prescription doses), do the ANALGESIC DRUGS
agents combat inflammation. It must also be clearly Aspirin and acetaminophen, when used properly at understood that patients frequently increase their OTC correct dosages, are very effective analgesic drugs for treating mild pain. Aspirin should be considered the The best advice a clinician can give to a patient who is first-choice agent; however, for the patient allergic to experiencing mild gastrointestinal (GI) problems sec- aspirin, acetaminophen is an excellent alternative, al- ondary to the use of an NSAID (OTC or prescription) is though it has insignificant anti-inflammatory activity.
to take the medication with a full glass of water and not Over-the-counter (OTC) analgesics are the mainstay to lie down for at least 30 minutes afterwards. A small for mild pain, and sales of these agents (ie, aspirin, acet- amount of food may be taken with the drug as well.
aminophen, ibuprofen, naproxen sodium, and keto-profen) total approximately $3 billion annuall Acetaminophen
For patients who cannot tolerate aspirin, acetamino- Over-the-Counter NSAIDs
phen is indicated, administered in doses similar to Aspirin. Aspirin, administered as a 650-mg dose (in
those used for aspirin. However, some caution is war- 2 tablets) every 4 hours, is the cornerstone of first-line drug therapy in various mild pain–related conditions, Acetaminophen tends to be better tolerated than such as minor arthritis flare-ups, mild tension–type aspirin in individuals who experience GI-related compli- headaches, and chronic minor low back pain. As with cations with analgesic agents. Acetaminophen has been all salicylates, aspirin is metabolized in the liver and is widely used largely because of its reputation for safety. Its highly albumin bound. Therefore, caution is warrant- pregnancy category is B, which means that animal stud- ed when aspirin is administered to a patient who is tak- ies are negative for fetal abnormalities, or animal studies ing an oral anticoagulant (OAC) drug, because OAC are positive while human studies are negative. agents are approximately 97% albumin bound. The Although its reputation for safety is deserved, acet- concomitant use of aspirin will displace a significant aminophen is not without risks. Hepatotoxicity is a sig- amount of the OAC drug from its inactive (albumin) nificant adverse drug reaction associated with the use binding site, causing an increase in the active dose of acetaminophen. Because many patients with pain take medications on a routine basis, it is the clinician’s Aspirin has a tentative pregnancy category label responsibility to warn of possible liver damage with as of D, which means that studies in pregnant women show positive evidence of human fetal risk. Aspirin also ophen daily over extended periods of time. Patients passes into breast milk. For infants and children (into should not take acetaminophen if they have experi- their teens), aspirin is contraindicated in the setting of enced an allergic reaction to it, have diminished liver viral infections, including influenza and chicken pox, function, have alcoholism, are fasting, or have substan- because it has been implicated in Reye’s syndrome.
tial kidney damage or loss of kidney function.
Complete blood counts should be monitored in pa-tients taking daily doses of aspirin. It is also recom- MONITOR THE USE OF NSAIDS WITH CARE
mended that kidney function/urine analyses be moni- NSAIDs account for approximately 20% to 25% of all reported adverse drug reactions. The chief symp- Perhaps the most significant fallacy about aspirin is tom is GI irritation. With increased dosing levels, there that it continues to be increasingly effective only up to will be an associated increase in the likelihood of an 650 mg. In fact, it has significant added analgesic effect adverse effect. Studies have shown that up to 4% of pa- up to 1000 Thus, if the standard 650-mg dose is tients treated with NSAIDs on a long-term basis will not effective, the clinician should increase the dose to develop GI complications, including ulcers, bleeding, 1000 mg (in adults) before trying an alternative anal- or perThe elderly and patients with a history of peptic ulcer disease are at highest risk.
Other over-the-counter NSAIDs. Ibuprofen, keto-
Also, substantial GI irritation is widely reported in profen, and naproxen sodium are excellent OTC anal- some patients taking even small amounts of NSAIDs. In
Hospital Physician August 2002 47
S u p e r n a w : P a i n M a n a g e m e n t : p p . 4 5 – 5 2 this case, it appears that a person sensitive to one NSAID ever, valdecoxib should also be considered for pain, will be sensitive to all NSAIDs. It is the responsibility of although it has not yet been approved by the US Food the clinician to recommend discontinuation of NSAID and Drug Administration for this indication. Addi- therapy before GI-related problems lead to significant GI tionally, celecoxib, rofecoxib, valdecoxib, and meloxi- bleeding. Even the nonoral form of these drugs can cam are approved for primary dysmenorrhea. Meloxi- cause significant GI irritation—because GI effects appear cam is significantly less COX-2 selective; therefore, it to be not just a local effect of the drug on the GI mucosa.
should be considered a more distant fourth choice.
As previously mentioned, patients should be instruct- If increasing the dose of an NSAID does not prove ed to take their OTC and prescription NSAIDs with a successful, an alternate NSAID may be substituted. It is full glass of water and not to lie down for at least 30 min- recommended that the second NSAID be selected utes afterwards; a small amount of food may also be from a different chemical class. Prescription-strength taken with the drug. This simple procedure will signifi- ibuprofen, ketoprofen, naproxen sodium, and naprox- cantly decrease the incidence of local GI-related distress, en are most commonly chosen. However, a COX-2 considering that these drugs are acidic. Although the inhibitor is recommended. Chemical classes of com- majority of cases of GI irritation from NSAIDs are sec- ondary to their pharmacologic effects, it must be under- specific information related to effective use of NSAIDs stood that most NSAIDs, including aspirin, are acids and have intrinsic local acidic effects.
Injectable NSAIDs, of which there are only two cur- Hepatotoxicity and nephrotoxicity are the only major rently available, ketoprofen and ketorolac—parecoxib adverse drug reactions associated with NSAIDs. (GI dis- may become available within a year—are not indicated tress is considered a minor adverse effect.) Therefore, for moderate pain, even if the pain is acute and would kidney and liver function should be monitored, especial- seem to demand a treatment that is more immediate ly in patients taking long-term doses or very large short- in action than are oral medications. It is important to term doses of NSAIDs or patients on concomitant doses remember that the drug is to be matched to the type and intensity of pain, and injectable NSAIDs are not Recently, a new category of NSAID, cyclooxygenase-2 appropriate for moderate pain that is effectively treat- (COX-2) inhibitors, has become available. The name of this class of drug is derived from the ability of theseagents to inhibit selectively the COX-2 enzyme. This AVOID PROBLEMATIC OPIOIDS
leads to a reduction in the conversion of substrates to There are three primary reasons for initiating po- prostaglandins that enhance pain transmission and tent opioid pharmacotherapy: (1) the pain is signifi- provoke inflammation, while not blocking the produc- cantly more debilitating than is moderate pain, (2) the tion of prostaglandins that cause platelets to aggregate pain is unresponsive to the milder opioids, or (3) the (clump) or that protect the GI mucosa. Therefore, patient has a history of success with the more potent these new drugs have more favorable adverse-effect opioids. When a decision is made to use a more potent profiles, because they do not significantly provoke opioid, it is prudent to consider carefully which agent GI irritation. However, they do not contribute to to use. Simply using what was most frequently used in platelet antiadhesin; thus, they do not possess the ben- the past or what has been used on the service is not an eficial cardiovascular effects of aspirin and traditional adequate justification for drug selection.
Special problems of neurotoxicity are most com- The 4 COX-2 inhibitor drugs most widely available mon with meperidine (Demerol) and pentazocine in the United States are celecoxib (Celebrex), rofecox- (Talwin)—problems that limit their usefulness beyond ib (Vioxx), valdecoxib (Bextra), and meloxicam 2 days (eg, in chronic pain or acute pain that persists (Mobic). Celecoxib, rofecoxib, and valdecoxib are ex- longer than 2 days). Meperidine is metabolized to nor- cellent choices for patients experiencing GI irritation meperidine, a well-known compound causing convul- with other NSAIDs. They are also excellent choices sions, especially with prolonged dosing, and renal com- when the analgesic dose must be pushed upwards, promise. Pentazocine has sigma-opioid activity and has which often provokes GI irritation when traditional provoked aberrant behavior in some persons.
NSAIDs are used. Celecoxib, rofecoxib, and valdecoxib Clearly, morphine is the gold standard in pharma- are indicated for osteoarthritis. Celecoxib and valde- cotherapy for significant, unremitting pain. It can be coxib are indicated for rheumatoid arthritis, and rofe- used without significant complications in long-term coxib and celecoxib are also indicated for pain. How- and progressive illnesses. Although constipation is a 48 Hospital Physician August 2002
S u p e r n a w : P a i n M a n a g e m e n t : p p . 4 5 – 5 2 Commonly Used Nonsteroidal Anti-inflammatory Drugs by Chemical Class Acetylated carboxylic
Acetic acids
Fenamic acids
Nonacidic compounds
Nonacetylated carboxylic
COX-2 inhibitors
Enolic acids
Pyrole acetic acid
commonly encountered adverse effect of morphine, the reports of drug-dependence syndrand sig- nificant respiratory deprhave been overem-phasized in cases of chrMost often, mor- Treat Cancer Pain Aggressively
phine is initiated at a modest dosage of 5 mg orally Simply stated, malignant pain does not resolve un- every 4 hours and titrated to achieve the desired effect, less the underlying malignancy is resolved. Too often, keeping the dosing schedule of 4-hour intervals intact.
patients with cancer are deemed to be “fragile,” and Hydromorphone (Dilaudid) and oxycodone are rea- consequently, their pain is left undertreated. There is sonable alternatives, if morphine is not acceptable.
some evidence that insufficiently treated cancer pain There are no kinetic and few therapeutic advan- actually hastens death, whereas adequate pain manage- tages to administering opioids by any other route other ment enhances both the quality and length of the life than orally, if feasible. In fact, in the Clinical Practice of the patient. There is simply no good reason to treat Guidelines of the Agency for Health Care Policy and Research, recommendations concerning opioid dosingfor malignant pain is “by mouth.It is clear that nei- Use Opioid Agonists
ther subcutaneous, intramuscular, nor intravenous ad- Nonagonist opioids, such as butorphanol, pentazo- ministration offers any real advantage in eliciting pain cine, nalbuphine, and buprenorphine, have no place in relief, and these routes usually require the participa- progressive cancer pain management. Nonagonists tion of a caregiver. Absorption in the GI tract is excel- all exhibit a ceiling effect by which increased doses pro- lent and rapid. Also, oral administration is significantly vide no additional analgesic effects. When cancer pain more acceptable to patients with cancer. reaches significant levels—levels that require opioids—an agonist (eg, morphine, hydrocodone, oxycodone, TAKE SPECIAL CARE WHEN TREATING PATIENTS WITH
hydromorphone, fentanyl, methadone) should be initi- ated. As agonists, these opioids exhibit no ceiling effect; Approximately 8 million Americans have cancer, therefore, as the pain level increases, the dose of the and there are approximately 1 million new cases of can- agonist can be increased to provide additional analge- cer diagnosed each yeaOne in every five deaths in sia. The doses of these agonists are limited only by their the United States—approximately 1400 per day— adverse sedating effects at higher levels. The adverse results from canceMore than 70% of patients with effects of dependence and respiratory depression do cancer experience or will experience substantial pain; not present themselves when the doses are progressive- however, pain can be managed effectively in 90% of the ly increased over time. However, one opioid agonist,
Hospital Physician August 2002 49
S u p e r n a w : P a i n M a n a g e m e n t : p p . 4 5 – 5 2 Commonly Used Nonsteroidal Anti-inflammatory Drugs and Their Prescription Doses Generic Name
Trade Name
Usual Prescription Dose
Dosing Schedule
immediately, then 15–30 mg every 6 hours, not to exceed 150 mg 1st day or 200 mg/day thereafter meperidine, should not be considered, because its ac- malignant pain (step 1). If the pain persists or increases tive metabolite is problematic when the drug is adminis- with the progression of the malignancy, a weak opioid, such as codeine, is recommended for moderate pain(step 2). If the pain persists or increases with the pro- Follow the World Health Organization 3-Step
gression of the disease, a potent opioid agonist is recom- Analgesic Ladder
mended (step 3). Additionally, at each level, coanal- The World Health Organization (WHO) has devel- gesics should be considered. These include NSAIDs oped cancer pain treatment strategies that have gained at the moderate or severe pain levels and psychotropic agents, such as antidepressant or anxiolytic drugs, at any pain level. Finally, as pain persists at the third step of the 50 Hospital Physician August 2002
S u p e r n a w : P a i n M a n a g e m e n t : p p . 4 5 – 5 2 analgesic ladder, the dose of the agonist can be progres- sively increased to mitigate the pain. If sedation occurs, astimulant, such as methylphenidate, may be added tomaintain wakefulness and add to the patient’s quality of life and family interactions, especially in the final days of ADMINISTER ANALGESICS AROUND-THE-CLOCK
For pain that will be sustained for long periods of time, studies have shown that administering analgesicson a regular schedule, or around-the-clock (ATC), pro- vides superior results when compared with administer-ing the medications on an as-needed basis. This is par- three principal rationales for this dosing regimen. First, with ATC analgesic administration, the effect of troughs in drug levels can be minimized. That is, as the levels ofthe first analgesic dose decrease and approach therapeu-tic threshold, a second dose can be administered toassure that drug levels never fall below the threshold.
This will keep the patient comfortable for long periodsof time. Second, ATC drug administration can diminishthe effects of the phenomenon known as pain wind-up.
Wind-up, in simple terms, is the phenomenon of addi- tive, unmitigated, rapid-fire pain impulses combining to cause significant pain. Third, ATC drug administrationallows the patient to “forget” the pain. That is, when apatient knows that persistent pain will re-present every 4 hours between doses of an analgesic drug, the antici- The World Health Organization 3-step analgesic pation of the pain can lead to discomfort and anxiety ladder. (Adapted with permission from World Health Organi- and, perhaps, a request for a greater dose of an anal- zation. Cancer pain relief and palliative care. Geneva: The Or- gesic agent than is necessary. Preempting pain is easier For significant pain that is unresponsive to NSAIDs (moderate-to-severe pain), long-acting opioids should medication administration can accomplish this, and it is be used, but they should never be administered on an accomplished most effectively with long-acting opioids.
as-needed basis. Sustained-release dosage forms have If breakthrough pain occurs, it should be treated with limited the need for repetitive dosing; long-acting opi- additional immediate-release medication. If break- oids may be administered every 12 hours. As with other through pain occurs routinely, the long-acting opioid dosage forms, the transdermal method (eg, fentanyl [Duragesic]) does offer the often-desired extendedduration of action; however, as with any extended-action CONCLUSION
dosage form, some complications may arise. Extra care Patients with pain represent a very challenging pat- must also be exercised when disposing of the patches, ient population to treat, yet if pain management strate- because significant amounts of unabsorbed drug may gies are successful, these patients are usually the most remain. It is, however, clear that the extended action appreciative of the clinician’s skills. Many patients with afforded by the fentanyl patch system does provide the chronic pain change physicians at least once during patient with some freedom from the need to receive therapy because of unmet expectations of the clini- cians. An understanding of the pain care principles Whenever possible, substantial cancer pain should be outlined in this article may serve the physician well in preempted, not treated after presentation. Only ATC meeting the needs of these patients.
Hospital Physician August 2002 51
S u p e r n a w : P a i n M a n a g e m e n t : p p . 4 5 – 5 2 REFERENCES
Portenoy RK. Opioid therapy for chronic nonmalignant McQuay HJ. Opioids in chronic pain. Br J Anaesth pain: a review of the critical issues. J Pain Symptom Tollison CD, Kriegel ML. Selected tricyclic antidepres- Lipman AG. Pain management. In: Herfindal ET, Gour sants in the management of chronic benign pain. South ley DH, Hart LL, editors. Clinical pharmacy and thera- peutics. 4th ed. Baltimore (MD): Williams & Wilkins; Kunz N. Report. 60th Scientific Sessions of the American Diabetes Association; San Antonio, Texas, 2000. Walsh TD, Baxter R, Bowerman K, et al. High-dose mor- Rosner H, Rubin L, Kestenbaum A. Gabapentin ad- phine and respiratory function in chronic cancer pain.
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