Pharmacological Management of Pain

Charles F. von Gunten, MD, PhD and Frank D. Ferris, MD

Systemic analgesics are the mainstay of pain management. Although many of these approaches have been developed for the management of cancer pain, they may be adapted to other chronic pain states. Many studies have demonstrated that pain is under-recognized and under-treated in geriatric populations.

Pain is a personal experience rather than a precise neurophysiological phenomenon. It is influenced by that person’s expectations, fears, hopes, coping styles, witnesses and attributed meanings. This combination of physiology, sociology, psychology and spirituality has complicated the study of pain and has led to the concept of "total pain".

In order to simplify the subject there has been an attempt to separate organic pain from psycho/social/spiritual pain. While this may be useful for heuristic and conceptual purposes, it has led to the unfortunate labeling of the former as "real" pain and the latter as "not real" pain. This represents both the inappropriate extrapolation of research on acute pain, particularly in laboratory animals, to the management of chronic pain, as well as to the general avoidance of emotional, psychological, social and spiritual issues by physicians trained in the scientific method. This may be particularly true in geriatrics, where physicians may regard some pain as "normal" in older adults or where its assessment may be challenging in the cognitively impaired. While this chapter reviews pharmacological management of organic pain, the reader should not suppose that this is the only important component of comprehensive pain management.

Acute vs. Chronic Pain

Appropriate pharmacological management of pain requires the clinician to distinguish acute from chronic pain. Acute pain has been defined as lasting less than 6 weeks and related to a discernible incident such as surgery or trauma. The natural history of acute pain, even in the absence of analgesia, is to resolve. Chronic pain has been defined as pain lasting more than 6 weeks and related to an ongoing pathophysiology. Intractable pain is that chronic pain whose cause, if known, is not expected to ameliorate. This may be related to ongoing pathophysiology within the nervous system itself as in neuropathic pain syndromes.

Recent data suggests that appropriate pharmacological management of pain may influence the overall severity and duration of pain. Further, documentation is accumulating that preemptive analgesia (analgesics administered prior to the inciting cause of pain such as an operation, e.g. an amputation) and early adequate treatment of acute pain diminishes the duration and severity of the acute pain and prevents the development of chronic intractable pain.

The WHO 3-Step Ladder for Pain Management

In 1988, as part of its efforts to improve public health worldwide, the World Health Organization (WHO) declared Cancer Pain management a worldwide emergency and adopted the Canadian 3-step ladder of analgesic agents for control of nociceptive pain. In addition to influencing government policies about pain control, this ladder provides a useful tool for illustrating and summarizing generally accepted approaches to conventional systemic analgesics. It is NOT a rigid clinical path that must be traversed in the care of every patient. The clinical judgment of a knowledgeable, experienced clinician is the most important determinant of appropriate pain therapy for any person with pain. The ladder, modified by the authors, is shown in Figure 1.

When initiating analgesia, it is important that the patient start at the appropriate step along the ladder – for mild pain start at step one, for moderate pain step two, for severe pain step three. As the severity of pain increases, maximize the dosing at the current step and then, if this is insufficient, move up the ladder.

Step One

Acetaminophen and the non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid (ASA) are the mainstay of step one of the WHO analgesic ladder for the management of mild pain. They obey first order kinetics and may be dosed up to recommended maximums (see Table 1). Many are available without prescription. Sustained release preparations or drugs with longer half-lives may encourage adherence.

Step Two

Several opioid analgesics are conventionally available in combination with either acetaminophen or ASA and are commonly used to manage moderate pain. They are listed in Figure 1 under step two of the WHO analgesic ladder. With the exceptions of propoxyphene (that truly has weak analgesic activity), tramadol (that has a unique combination of very weak opioid activity with other analgesic properties) and codeine (that has 1/10 to 1/12 the potency of morphine), the opioids in this class are close in potency to morphine (mg for mg). However, they have been termed "weak" opioids because, in combination, they have a ceiling to their analgesic potential due to the maximum amounts of acetaminophen or ASA that can be administered per 24 hours (i.e. 4 gm acetaminophen per 24 hours)

The combination medications of step two all obey first order kinetics and may be dosed up to recommended maximums (see table 2). The potential side effects are those of the component drugs.

Frequently, patients are given prescriptions for several step two drugs even though pain is poorly controlled. This usually occurs when physicians are reluctant to prescribe a step three strong opioid. Aside from propoxyphene, there is no evidence that maximal dosing of any one "step two" medication is better than another and trials of several step two medications are likely to prolong the patient’s pain. In addition, when a step two drug inadequately relieves pain, patients may combine two or more medications, or take more than the prescribed amount in an attempt to obtain pain relief. In doing so, they may unknowingly put themselves at increased risk for significant toxicity from either the acetaminophen or ASA component of the medication.

If pain persists, or increases, despite a maximum dose of a step two drug, a step three drug should be prescribed instead.

Step Three

The pure agonist opioid analgesics comprise step three of the WHO analgesic ladder. Morphine is the prototypical drug because of its ease of administration and wide availability. Other widely prescribed opioids are listed in Figure 1. Many patients with chronic pain are best managed with an appropriately titrated strong opioid that is combined with one or more coanalgesics. In contrast with the step-one and step-2 analgesics, there is no ceiling effect or upper limit to the dose of opioids when titrating to relieve pain.

"Step Four"

Several studies of the WHO 3-step ladder have demonstrated that its application results in the adequate control of up to 90% of patients with cancer pain. Several authors have informally invoked "step four" to indicate approaches that should be reserved for patients whose pain is not controlled by competent use of the analgesic approaches outlined in the first three steps. In general, "step four" involves invasive approaches for pain relief that can be summarized as follows.

Subcutaneous (sc) or intravenous (iv) administration of opioid analgesics and coanalgesics may be required for patients where oral (po), buccal mucosal, rectal (pr), or transcutaneous approaches are not possible or practical, or where doses of oral opioids lead to undesirable side effects. Side effects may be minimized as a result of the uniform delivery of the drug parenterally, the change in route of administration or the reduction in first pass metabolite production.

Subcutaneous administration may be preferable to intravenous approaches as it results in equivalent serum levels and analgesia without the risks of thrombosis or infection, and is much easier to deliver, for much less cost.

Intraspinal administration of opioid analgesics either epidurally or intrathecally may be required in selected patients.

Intraventricular application of opioid analgesics and other drugs has been investigated for selected central pain syndromes.

Neuroablative techniques such as peripheral neurolytic blockade, ganglionic blockade, cordotomy and cingulotomy may be appropriate in highly selected patients.

Common Analgesic Agents


Despite its wide use, the precise mechanism of action of remains unclear. Although it is analgesic and antipyretic, it is not anti-inflammatory, at least systemically. Its analgesic activity is at least additive to other analgesic agents, including the NSAIDs and opioids.

Acetaminophen is associated with significant liver toxicity. It is generally recommended that the total dose not exceed 4 grams per 24 hours.

NSAIDs including ASA

NSAIDs are antiinflammatory through their ability to inhibit the enzyme cyclooxygenase that catalyzes the conversion of arachidonic acid to prostaglandins and leukotrienes. Their effect is to decrease the levels of these inflammatory mediators that sensitize nerve endings to painful stimuli. Because analgesia from NSAIDs is achieved through a different mechanism from the opioids and other adjuvant analgesics, they may be combined with these drugs to achieve better pain relief than with a single drug alone. Primary analgesia may be achieved at lower doses than those required for antiinflammatory action. Therefore, when used as an adjuvant for their antiinflammatory effects, maximum doses should be used.

The side effects of the NSAIDs are related to their mechanism of action. Inhibition of cyclooxygenase leads to inhibition of platelet aggregation, decreased cytoprotection in the gastric mucosa, and decreased renal perfusion. Consequently, bleeding and renal failure are important side effects. The dyspepsia and abdominal pain that limit use of the NSAIDs in some patients do not correlate with significant gastric erosions and gastrointestinal bleeding. Similarly, the use of an H2 blocking antacid (e.g. cimetidine or ranitidine) to treat NSAID dyspepsia and abdominal pain does not prevent gastric erosions and gastrointestinal bleeding. Only misoprostol, which reverses the effect of NSAIDs on the micro-arteriolar circulation of the stomach, has been shown to heal gastric erosions and reduce the risk of significant gastric bleeding.

The non-acetylated salicylates (choline magnesium trisalicylate and salsalate) and nabumetone do not significantly affect platelet aggregation. They may be useful in patients who are thrombocytopenic and for whom other NSAIDs are contraindicated. Sulindac is thought to be least likely to induce renal failure because of its minimal effect on prostaglandin synthesis at the level of the proximal renal tubule.

In contrast with the opioids, the NSAIDs and acetaminophen have a ceiling effect to their analgesic potential, do not produce pharmacological tolerance, and are not associated with physical or psychological dependence.


Opioid analgesics act by binding to opioid receptors of three subtypes (mu, kappa, and delta). Traditionally, analgesia is thought to be modulated principally by opioid action at central mu receptors. Recent work suggests that opioids may have other important sites of action. The opioid analgesics in common usage may be divided into those which are full mu agonists, partial agonists and mixed agonist-antagonists. The pure agonist drugs are the most useful in chronic intractable pain. Recent clinical trials suggest they are safe and effective in geriatric populations for chronic pain conditions other than cancer.

Opioids to Avoid

The mixed agonist-antagonist opioids (such as pentazocine, butorphanol and nalbuphine) and the partial agonist opioids (such as buprenorphine) are poor choices for patients with severe pain. They have no advantages over the pure agonist opioids. Besides having a ceiling effect to the analgesia they produce, they have the significant disadvantage that, if combined with a pure opioid agonist, they may precipitate acute pain and opioid withdrawal symptoms.

Meperidine (Demerol®) is a synthetic pure agonist opioid that is widely used in the postoperative management of acute pain. However, its continued use has been questioned for three reasons. First, because of its short duration of action in comparison with morphine or other pure agonist opioids it must be dosed too frequently to provide convenient, adequate analgesia. Second, because its oral absorption is unpredictable, a reliable oral dose cannot be prescribed which corresponds to parenteral doses. Third, and most significant, the major liver metabolite normeperidine, which has a longer half-life (approximately 6 hours) than meperidine (approximately 3 hours), accumulates with repeat dosing for analgesia and frequently causes significant sub-clinical or clinical toxicity, including impaired concentration, restlessness, agitation, excessive dreams, hallucination, myoclonic jerks or even seizures. This accumulation is particularly accentuated in patients with compromised renal function. The assertions that meperidine is associated with less constipation or spasm of the sphincter of Oddi are not well supported. Its use is best limited to small doses (25-50mg) parenterally to treat rigors associated with fever, drugs, or blood product transfusions.

Analgesic Pharmacology

Appreciation of general pharmacological principles is essential if systemic analgesics are to be used appropriately to achieve pain relief.

Routes of Administration

The preferred route for analgesic administration for the management of pain is oral. This route provides the simplest, least expensive way to manage up to 90 percent of all cancer pain. When the oral route is not available, analgesics can be administered buccally and rectally without resorting to more expensive and invasive routes of delivery. In a small number of patients, subcutaneous, intravenous, or intraspinal administration may be required.

Routine Dosing for Constant Pain

When managing pain, it is important to distinguish between constant and intermittent pain. For pain that is constant, analgesics should be prescribed on a regular schedule at doses sufficient to keep the pain controlled. Dosing solely on an "as needed" or "prn" basis is inappropriate as it subjects the patient to unnecessary pain and may increase both the patient’s anxiety and the total dose required to control the pain.

Most of the short-acting drugs used for analgesia, particularly acetaminophen, the NSAIDs including ASA and the opioids, follow first-order kinetics. When prescribing them on a routine schedule, they should be administered once every half-life in order to achieve steady state and maintain constant serum levels, i.e. q4h for po dosing. Methadone, with its longer half-life is administered q8-12h.


When initiating, titrating or changing analgesic therapy, drugs that follow first order kinetics take five (5) half-lives to reach pharmacological steady state. Changes in dosages should only be made once the serum level has reached steady state, e.g. once every 20-24 hours when morphine is given po, or even sc. Waiting longer will not improve pain control. Increasing dosages before steady state is reached may lead to unnecessarily high serum levels and undesired side effects.

Sustained Release Products

Sustained release medications should not be used to adjust or titrate a patient’s uncontrolled pain. Using them for titration unduly prolongs the process to bring the pain under control. However, once the pain is controlled, changing to a sustained release product may enhance the patient’s quality of life and improve compliance and adherence due to the decreased frequency of dosing (e.g. q8h, q12h, q24h, etc.).

Sustained-release preparations of codeine, hydromorphone, morphine and oxycodone are (or soon will be) available for po administration (as will morphine for pr administration) and should be administered in accordance with the instructions of the manufacturer. Fentanyl is available as a transdermal preparation that can usually be administered every 72 hours.

Breakthrough or Rescue Dosing for Intermittent Pain

Intermittent pain may occur because of activity (incident pain) or a change in the severity of the pain. If the duration and severity of the intermittent pain is sufficient, extra short-acting doses of the same or similar medication (breakthrough or rescue doses) on an "as needed" or "prn" basis may be appropriate. If a patient requires more than 2-4 breakthrough doses on a regular basis, then the routine dose should be adjusted upwards. For intermittent pain of short duration (seconds to a few minutes) breakthrough dosing, particularly of the opioids, may lead to undesired side effects without increased analgesia.

For most analgesics the time to reach maximum serum concentration (Cmax) after a given dose of analgesic correlates closely with the maximum pharmacological effect. Breakthrough doses of an analgesic can be given safely with a frequency equivalent to the time required to reach Cmax. For example, a bolus of IV morphine achieves its maximum serum concentration (Cmax) in 5-10 minutes whereas po morphine achieves its maximum in 45-65 minutes. Therefore, breakthrough doses can be given q5-10min IV, q30min sc or q60min po. Making the patient wait any longer when the pain is not controlled simply prolongs the time required to establish optimal pain control.

The size of the breakthrough dose should be related to the routine dose. For the strong opioids such as morphine, hydromorphone and oxycodone, a simple rule-of-thumb is: administer 10% of the total 24-hour dose per breakthrough. The dose is then adjusted as the routine dose changes or as the intensity of the intermittent pain requires.

Equivalent Doses

The relative abilities of opioid analgesics to relieve pain have been correlated (Table 3). It is important to bear in mind that these relationships are not scientifically precise, as there is significant inter-patient variability. Further, the data from which these equivalencies are derived are often not directly applicable to chronic cancer pain. Nevertheless, the equal analgesia tables are useful to approximate the dose of a new analgesic when changes are contemplated. The dose should then be adjusted based on patient response.

When changing between opioids, there is incomplete cross-tolerance and some advocate a 25-50% reduction in the new drug after calculating the equal analgesic dose to account for this.

Attempts have been made to correlate the relative analgesia provided by acetaminophen, the NSAIDs and the opioids. Ketorolac 10 mg orally seems to be roughly equivalent to 60 mg codeine/650 mg acetaminophen in cancer pain.

When changing routes of administration, differences in opioid metabolism (e.g. less first pass catabolism iv/im/sc compared to po) necessitate adjustments to the opioid dose as indicated in table 3. For example, an equivalent dose of morphine iv/im/sc will be one-half to one-third that given po.


Acetaminophen is metabolized in the liver and becomes toxic if catabolic pathways become saturated (usually at doses > 4 gm per 24 hours). Therefore its use in liver failure or in the setting of significant liver injury is contraindicated.

ASA and many of the commonly used NSAIDs (such as naproxen and ibuprofen) are also primarily metabolized and/or eliminated by the liver (exceptions include piroxicam).

The opioids are conjugated in the liver and > 90% are excreted renally. While most of the opioid metabolites are inactive, some (such as morphine 6-glucuronide) have analgesic activity and several may be responsible for some observed side effects. Mild elevation in transaminases should not significantly impact opioid dosing. Patients with severe liver failure should have their opioid doses decreased and dosing intervals increased.

Impaired renal excretion will reduce opioid clearance and may lead to buildup of metabolites. Analgesia will be sustained and risk of side effects increased. To reduce the risk of buildup, patients receiving opioids should be well hydrated and maintain adequate urine output. If renal function is impaired, opioid doses should be decreased and dosing intervals increased. The patient with anuria may require very little extra opioid to maintain analgesia. Routine dosing should be discontinued.

Opioid Side Effects

The common and uncommon side effects of the opioid analgesics are listed in Table 4.

Common side effects of the opioid analgesics are easily managed. In the majority of patients, pharmacological tolerance develops to all of the common side effects except constipation, within one to two weeks. Consequently, nausea and vomiting may be treated expectantly with antiemetics for the short period that these symptoms are problematic. If nausea and/or vomiting persist, simply changing the opioid or the route of administration may resolve the problem.

Similarly, patients should be counseled that the drowsiness they experience when initiating an opioid will usually dissipate after the first week or so. Patients can often tolerate a little drowsiness if they are assured that it won’t persist for the entire time they are taking opioid analgesics. In fact, once a stable dose of an opioid has been reached, drowsiness will likely settle completely, function will normalize and most patients on a stable dose of opioid may safely drive a car. Persistent somnolence may be managed by ensuring adequate hydration and renal clearance, changing to a sustained release product to minimize peak effects, changing the opioid, changing the route of administration or by adding a psychostimulant (such as methylphenidate or pemoline).

As patients given opioid analgesics will not develop tolerance to constipation, they should be treated with cathartic laxatives (e.g. Senna or Bisacodyl), osmotic laxatives (e.g. magnesium salts or lactulose) or prokinetic agents (e.g. metoclopramide or cisapride) on a routine basis. Simple stool softeners (e.g. sodium docusate) are usually ineffective.

Persistent side effects of the opioids seem to be somewhat idiosyncratic to the drug and individual. Simply changing to an alternate opioid at an equal analgesic dose will often clear the problem.

The uncommon side effects of the opioids are also manageable. The dysphoria and confusion that occasionally occur may be managed by ensuring adequate hydration and renal clearance (thereby minimizing metabolite buildup), lowering the opioid dose, changing the opioid analgesic or by adding low doses of a neuroleptic drug such as haloperidol, chlorpromazine or risperidone.

The pruritus and urticaria that occurs with opioids is not immune mediated, but a non-specific release of histamine from mast cells in the skin. This may be managed with long-acting antihistamines or by changing to an alternative opioid analgesic. True allergy presenting as bronchospasm leading to anaphylaxis is extremely rare. Most patients who report allergy have had poorly managed side effects (usually nausea/vomiting and/or constipation) or too much medication too fast (leading to drowsiness and/or confusion).

The risk of respiratory depression from opioid analgesics in patients with pain is frequently misunderstood. Pain is a potent stimulus to breathe and a significant stressor. While we cannot be certain of the effects of the first dose in an opioid naïve patient, patients develop pharmacological tolerance to the respiratory depressant effects of opioids over the same time course as other side effects. Consequently, in the patient taking opioid analgesics for any significant length of time, it is difficult to demonstrate significant respiratory depression even with large doses of opioids.

Too frequently opioids have been withheld or under-dosed because of unsubstantiated fear of respiratory depression or the mismanagement of side effects. In the patient with uncontrolled pain, narcotic analgesics can be judiciously but expeditiously and safely titrated until adequate relief is obtained or intolerable side effects encountered.

Opioid Excess/Overdose

In the setting of pain management, increasing opioid excess presents first as mild drowsiness, proceeds to persistent somnolence, then to a poorly arousable state and finally to respiratory depression. These changes may be associated with increasing restless, agitation, confusion, dreams, hallucinations, myoclonic jerks or even sudden onset of seizures.

When assessing a patient for respiratory depression, it is important to remember that a respiratory rate of 8-12 is frequently normal, particularly at nighttime. If early, or even moderate excess is present without major compromise, the opioid can be held and normal metabolism will clear the excess opioid, particularly if the poorly hydrated patient is adequately rehydrated. Naloxone reversal is not normally necessary.

If the patient is not arousable, has a respiratory rate less than 6-8 per minute or there is significant hypoxemia or hypotension present, opioid reversal with naloxone may be warranted. Dilute a 0.4 or 1.0 mg ampule of naloxone with 10 cc of saline and administer 0.1-0.2 mg IV boluses every 1-2 minutes. Sc or po administration is not appropriate. As naloxone has a high affinity for opioid receptors, titration any faster, or with larger boluses, may precipitate acute opioid withdrawal that presents as an acute pain crisis, psychosis or severe abdominal pain and precipitates pulmonary edema or even myocardial infarction. Only if several 0.1-0.2 mg boluses are ineffective should the bolus size be increased.

Naloxone has a high affinity for lipids and will redistribute itself into adipose tissue within 10-15 minutes of administration. Any improvement frequently appears to disappear within this time frame and signs of toxicity return. Repeated naloxone dosing may be necessary to sustain the reversal until the patient has cleared sufficient of the opioid to be out of danger. If the overdose is severe and considerable naloxone is required, a continuous infusion of naloxone may be required until the crisis is over.

If a patient, who has been well managed on a stable dose of opioid for some time suddenly develops signs of overdose, the opioid should be stopped and sepsis or other causes should be ruled out. It is unlikely that the opioid alone will be the cause of the "effective overdose".

Addiction vs. Tolerance

Addiction, the psychological dependence on the drug, is also a vastly overrated and misunderstood consequence of using opioid analgesics. In patients with chronic pain, the incidence of addiction is less than 1:1000 and is usually related to preexisting dependency. Because of its rarity, it is not listed in Table 1 with the other side effects of the opioids.

Physical dependence, meaning the development of a withdrawal syndrome upon abrupt discontinuation of the drug, is not evidence of addiction. Physical dependence occurs over the same time course as tolerance develops to the side effects of the opioid analgesics and is the result of changes in the numbers and function of opioid neuro-receptors in the presence of exogenous opioid.

If opioid analgesics are tapered instead of abruptly withdrawn, withdrawal symptoms do not occur. Usually the opioid dose can be reduced by 50-75% q2-3days without ill effect. Occasionally a small dose of a benzodiazepine (e.g. 0.5-1.0 mg of lorazepam) or of methadone (with its longer half-life) may be necessary to settle the feeling of slight uneasiness or restlessness that accompanies the tapering process. If restlessness or agitation is anything more than very mild, the rate of tapering should be slowed.

Adjuvant Pain Medicines

Adjuvant analgesics are drugs used to enhance the analgesic efficacy of opioids, treat concurrent symptoms that exacerbate pain, and/or provide independent analgesia for specific types of pain. They may be used in all stages of the analgesic ladder. Some of the adjuvants, such as acetaminophen, the NSAIDs, the tricyclic antidepressants and perhaps the antiepileptics have primary analgesic activity themselves and may be used alone or as coanalgesics.

Two cancer pain syndromes bear particular mention in this regard. Bone pain from bone metastases is thought to be, in part, prostaglandin mediated. Consequently, the NSAIDs and/or steroids may be particularly helpful in combination with opioids. Cord compression should always be considered if the pain is severe, increasing quickly or associated with motor, bowel or bladder dysfunction.

Neuropathic pain is rarely controlled with opioids alone. The tricyclic antidepressants, antiepileptics and steroids are often required in combination with the opioids to achieve adequate relief. Commonly used agents are listed below with a few comments about their use

NSAIDs and/or acetaminophen may be added to the opioids for adjuvant analgesia, particularly when inflammatory or peripheral mechanisms are thought to be responsible for the painful stimulus.

Corticosteroids provide a range of effects including anti-inflammatory activity, mood elevation, antiemetic activity and appetite stimulation. They reduce pain both by their anti-inflammatory effect of reducing arachidonic acid release to form prostaglandins as well as decreasing swelling and pressure on nerve endings. Undesirable effects such as hyperglycemia, weight gain, myopathy, and dysphoria or psychosis may complicate prolonged therapy.

Anticonvulsants (such as carbamazepine, valproate, clonazepam, phenytoin, and gabapentin) are used either alone, or in addition to opioids or other coanalgesics to manage neuropathic pain. They have been particularly advocated for neuropathic pain with a shooting or lancinating quality (such as trigeminal neuralgia or nerve root compression).

Tricyclic antidepressants (such as amitriptyline, desipramine, imipramine, nortriptyline) are useful in pain management in general, and neuropathic pain in particular. They have innate analgesic properties and are effective through mechanisms that include enhanced inhibitory modulation of nociceptive impulses at the level of the dorsal horn. If the anticholinergic side effects of tertiary amine tricyclics (amitriptyline, imipramine) are undesirable or troublesome, the secondary amine tricyclics (nortriptyline, desipramine) may be effective analgesics and produce fewer side effects. The selective serotonin reuptake inhibitor class of antidepressants has not been shown to be useful in similar ways to the tricyclic antidepressants.

Bisphosphonates (such as pamidronate) and calcitonin have been used as adjuvant analgesics in the management of bone pain from bone metastases. In cancer, bone pain is caused in large part by osteoclast-induced bone resorption rather than the direct effects of the tumor on periosteal or medullary nerve endings. Both the bisphosphonates and calcitonin inhibit osteoclast activity on bone and have been reported to reduce pain significantly in at least some patients.

Neuroleptic medications (such as haloperidol, chlorpromazine or risperidone) and anxiolytics (such as lorazepam) are used for the management of specific psychiatric disorders that complicate pain management such as delirium, psychosis, or anxiety disorders. With the exception of methotrimeprazine and clonazepam, none have been shown to have intrinsic analgesic activity.



Appropriate pharmacological intervention can effectively manage most pain. Medications should be chosen appropriately, administered using the pharmacological principles that guide their usage and patients monitored closely for undesired side effects. Some frequently associated side-effects may also require preventative intervention.

3 Strong Opioid_______

Severe pain








+ Adjuvants

2 "Weak" Opioid_______

Moderate pain







+ Adjuvants

1 Non-Opioid____

Mild Pain

Acetylsalicylic acid


Nonsteroidal antiinflammatory
drugs (NSAIDs)

{Tricyclic antidepressants}


+ Adjuvants

Figure 1. WHO 3-step ladder for pain management (Modified by Authors)



Table1: Selected Step-1 Analgesics

Drug Suggested maximum dose
Acetaminophen (APAP, Tylenol) 650 mg po q4h
Acetylsalicylic Acid (ASA, Aspirin) 650 mg po q4h
Ibuprofen (Motrin) 800 mg po qid
Choline magnesium trisalicylate (Trilisate) 1500 mg po tid
Diclofenac (Cataflam)
Diclofenac-extended release (Voltaren)
50 mg po qid
75 mg po tid
Diflunisal (Dolobid) 500 mg po tid
Etodolac (Lodine) 400 mg po tid
Indomethacin (Indocin) 50 mg po qid
Ketoprofen (Orudis) 75 mg po qid
Nabumetone (Relafen) 1 g po bid
Naproxen (Naprosyn) 500 mg po tid
Oxaprozin (Daypro) 1800 mg po qd
Sulindac (Clinoril) 200 mg po bid
Salsalate (Disalcid) 1500 mg po tid
Ketorolac (Toradol) 60 mg IM/IV then 30 mg IV/IM q 6h
10 mg po qid
not to exceed 5 days



Table 2: Selected Step-2 Analgesics

Drug Suggested Maximum Dose
Codeine 30 mg/ 325 mg APAP (Tylenol #3)
Codeine 30 mg/325 mg ASA (Empirin #3)
2 po q4h
Hydrocodone 5 mg/500 mg APAP (Vicodin)
Hydrocodone 10 mg/650 mg APAP (Lortab)
2 po q6h
1 po q 6h
Oxycodone 5 mg/325 mg APAP (Percocet)
Oxycodone 5 mg/325 mg ASA (Percodan)
2 po q4h
Tramadol (Ultram) 50 mg 2 po q6h

Table 3: Equal Analgesia

Oral Dose (mg) Analgesic Parenteral Dose (mg) IV/SC/IM
150 Meperidine 50
100 Codeine 60
15 Hydrocodone -
15 Morphine 5
10 Methadone 5
10 Oxycodone -
4 Hydromorphone 1.5
2 Levorphanol 1
- Fentanyl 0.050

Table 4: Side Effects of Opioid Analgesics

Common Uncommon
Constipation Dysphoria/delirium
Nausea/vomiting Bad dreams/hallucinations
Drowsiness Pruritus/urticaria
Dry mouth Urinary retention
Sweats Myoclonic jerks/seizures
Respiratory depression

Suggested Reading

  1. Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain. Clinical Practice Guideline No. 9. AHCPR Publication No. 94-0592. Rockville, MD. Agency for Health Care Policy and Research, US Department of Health and Human Services, Public Health Service, March 1994.
  2. Patt, RB. Cancer Pain. JB Lippincott Company, Philadelphia, 1993.
  3. Doyle D, Hancks G, MacDonald N. Oxford Textbook of Palliative Medicine. Oxford University Press, New York 1997.
  4. Levy MH Pharmacologic treatment of cancer pain. N Engl J Med 1996;35:1124-32. [Citation]
  5. Bonica JJ. Cancer Pain. In: The Management of Pain. Ed John J Bonica. Lea & Febiger. Philadelphia 1990 pp400-460.
  6. Librach SL and Squires BP. The Pain Manual: Principles and issues in cancer pain management. Pegasus Healthcare International. Toronto 1997

Copyright ©1999. Northwestern University. All Rights Reserved.
Edited by the Buehler Center on Aging, McGaw Medical Center.
For information regarding content contact:
James R. Webster,

Published electronically by the Galter Health Sciences Library.
For information regarding publication contact:
James Shedlock,

Last Updated: June 9, 1999