Nusayba Bagegni, Amy Sheldahl, and Maria C. Dans
GENERAL PRINCIPLES
· Pain is one of the most common complaints evaluated by physicians. It is the presenting symptom of myriad medical conditions. Some of these conditions are curable, but in many cases, the role of the physician is not to cure the disease but to control the pain associated with it.
· Historically, treatment of pain has been limited by fears of addiction and dependence as well as societal conventions on the role of pain in character development and the dying process. Pain therapy has evolved as physicians have come to view treatment of pain as an essential component of patient care—a task as important as treatment of the disease itself.
· This chapter will discuss the general principles of pain management. While many of these concepts have been developed for the treatment of chronic cancer pain, they can be applied to patients experiencing pain associated with many other disease processes.
Definition
The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage.”1 Pain is extremely subjective by nature, so a more clinically accessible definition might be that pain is whatever the patient says it is.
Classification
· Classification of pain into subsets based on mechanism and time course can guide therapy. Pain in a given patient often falls into several of these categories; all relevant categories should be addressed for adequate treatment.
· Acute pain
o Acute pain is associated with a recent, often reversible etiology.
o Examples include joint injuries, postoperative pain, and pain associated with acute infection or trauma.
· Chronic pain
o Chronic pain results from irreversible or not easily reversible etiologies.
o Examples include pain due to malignancy, some forms of low back pain (LBP), and severe degenerative joint disease.
· Nociceptive pain
o Nociceptive pain is classically associated with acute pain and injury. Tissue damage via mechanical, chemical, or thermal processes triggers activation of nociceptive pain fibers.
o Pain may be described as sharp, gnawing, or aching. It is usually well localized and often worse with movement.
· Neuropathic pain
o Neuropathic pain (also referred to as neurogenic pain) is due to nerve injury in the central or peripheral nervous system. All pain is modulated by central pain processing pathways; in neuropathic pain, there is frequently an abnormality caused by tissue damage or disease in the processing pathways that contributes to the ongoing pain.
o Pain may be described as burning or stinging and may be accompanied by numbness, tingling, allodynia (pain in response to a stimulus, i.e., normally innocuous), or hyperalgesia (increased sensitivity to pain).
· Visceral pain
o Visceral pain is due to stretching, crushing, or ischemia of organs supplied by visceral nerve fibers.
o Pain may be described as squeezing, cramping, dull, or aching. It is frequently poorly localized; occasionally referred to a cutaneous dermatome supplied by the same nerve roots; and often associated with autonomic symptoms including nausea and vomiting.
Epidemiology
· LBP accounts for one-fifth of visits to medical clinics and is second only to upper respiratory illnesses as a symptom-related reason for a visit.2,3
· Up to 75% of patients with advanced cancer report being in pain.4
· Up to 50% of patients with cancer or their surrogates reported moderate to severe pain in last 3 days of life.5
· Pain is one of the most feared symptoms of cancer, and cancer-related pain is more likely to be poorly controlled in the elderly (age >70), minorities, and patients with a good functional status.6,7
Pathophysiology
· Painful stimuli activate nociceptors in the skin, joints, organs, and other tissues. Nerves transmit these signals to the central nervous system.
· Synaptic transmission and central pain processing pathways modulate the transmission of pain signals, and pain is ultimately experienced via the central nervous system.
· Pain may be due to injury at any level of the pain pathway, including tissue damage that stimulates nociceptors, injury to nerves that carry or modulate pain signals, and damage to central nervous system neurons involved in pain processing.
DIAGNOSIS
Clinical Presentation
· A thorough history is paramount for the accurate diagnosis and treatment of pain. A history should include information regarding the patient’s pain as presented in Table 37-1.
· Pain severity is best assessed by patient self-report and may be aided by visual analogue scales, numerical rated scales, and/or verbal rated scales.8
· Physical examination can aid in diagnosing some causes of acute pain, such as joint injury or infection.
· The physician should also assess for signs of a source of chronic pain, such as cancer or neuropathy.
· All patients should be assessed for signs of hemodynamic instability, peritonitis, or other causes of acute pain, which require emergent evaluation for stabilization.
· Acute pain is typically accompanied by physical signs, such as tachycardia, diaphoresis, hypertension, and obvious physical discomfort. Patients with chronic pain often have few physical signs of pain.
· Pain may exist without physical manifestations.
TABLE 37-1 Pain History
Diagnostic Testing
· No diagnostic test is available to provide objective assessment of pain.
· Diagnostic testing is indicated when the history and physical examination point toward sources of pain, which may be amenable to curative treatment.
· Additional testing is sometimes indicated for pain that may require specialized interventions such as surgery, although a discussion of this topic is beyond the scope of this text.
TREATMENT
· A thorough history, physical examination, and diagnostic tests as indicated should identify potentially curable causes of pain. If treatable causes of pain are discovered, pain control should be pursued along with curative therapy.
· When no curable cause of pain is found, therapy should proceed with a combination of nonpharmacologic treatments, medications, and possibly targeted procedures, if applicable.
· All interventions and therapies should be tailored to meet the needs of each patient. Complete relief of pain may not be possible; satisfactory control of pain, however, may allow participation in important activities or other specific goals of the patient.
Historical Perspective
· The World Health Organization (WHO) pain ladder, developed in 1982, was the result of a public health initiative designed to provide a framework to improve pain control for patients with cancer worldwide. In this simple algorithm, treatment of pain is addressed in three steps. If pain persists at a given step, treatment is advanced to the next step. All steps recommend the use of adjuvant therapy, if indicated.
o Step 1 (mild pain): Nonopioid analgesic, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs).
o Step 2 (moderate pain): Weak opioid +/− nonopioid analgesic.
o Step 3 (severe pain): Strong opioid +/− nonopioid analgesic.
· The WHO ladder helped change attitudes toward pain management and heightened physician awareness of the importance of pain management.
· With rational pain management, addiction and tolerance are less likely to be clinical problems.9
· While most patients can achieve improved pain relief using this algorithm, the WHO ladder does have limitations.
o It does not include an assessment step.
o It does not take into account targeted therapy for neuropathic pain.
o It does not allow for nonpharmacologic strategies.
o While it is common practice to follow the WHO’s recommendation to combine NSAIDs with opioids, there is no evidence base to support a clinical difference in pain relief when opioids are given in combination with NSAIDs as compared with either drug alone.10
Basic Pain Management Principles
· For acute self-limited pain, short-acting agents can be used as needed.
· Analgesics may be used before engaging in activities that provoke pain, for example, dressing changes or physical therapy.
· For chronic pain, adequate analgesia is best obtained with a combination of long-acting basal pain medication and doses of short-acting medications as needed for breakthrough pain.
o Breakthrough doses should be 5% to 15% of total daily dose.
o Basal dose should be increased in patients consistently requiring >2 to 3 breakthrough doses per day.
o Dose escalation for inadequate pain control should increase the 24-hour dose by 30% to 50%.
· While neuropathic pain is responsive to opioid therapy, adjuvant therapy with antidepressants or anticonvulsants may confer additional benefit.11
· Start with the lowest effective dose of medication and titrate up as needed.
· Be careful to avoid acetaminophen overdose when using opioid/acetaminophen combination pills.
Medications
Nonopioid Analgesics
· Nonsteroidal anti-inflammatory drugs
o NSAIDs exert antipyretic, analgesic, and anti-inflammatory effects via inhibition of cyclooxygenase isoenzymes (COX1 and/or COX2 depending on the agent), which leads to decreased production of thromboxane and prostaglandins via the arachidonic acid pathway.
o NSAIDs are effective for mild pain, especially pain with an inflammatory component.
o Most NSAIDs have an analgesic ceiling effect, a dose above which there is little improvement in analgesia, but increased risk of adverse effects.
o These drugs are relatively contraindicated in patients with renal insufficiency or with a history of peptic ulcer disease.
o Adverse effects of NSAIDs include gastrointestinal tract bleeding via gastritis or ulcer formation, platelet dysfunction, and renal insufficiency. Aspirin may precipitate bronchospasm in patients with severe asthma.
o Gastrointestinal side effects may be reduced by using proton pump inhibitors or H2-blockers to suppress gastric acid production.
o Details regarding commonly used NSAIDs are presented in Table 37-2.
· Acetaminophen
o Acetaminophen exerts analgesic and antipyretic effects. Its exact mechanism of action is poorly understood.
o Analgesic dosing is 325 to 650 mg PO every 4 to 6 hours or 1 g 3 to 4 times/day. Maximum daily dose should not exceed 4 g/day for patients with normal hepatic function; patients with liver disease should not take >2 g/day. The recommended maximum dose for patients >70 years of age is 3 g/day.
o An analgesic ceiling effect likely occurs at doses of 1 g.12
o The major adverse effect of acetaminophen is liver toxicity, ranging from mild transaminitis to fulminant hepatic failure. Patients with underlying liver disease or heavy alcohol use can experience liver damage at lower doses.
o Acetaminophen is available in tablet, oral liquid, intravenous, and suppository forms.
TABLE 37-2 Commonly Used Nonsteroidal Anti-Inflammatory Drugs
Opioids
· Opioids exert analgesic effects to alter pain perception via opioid receptors in both the central nervous system and the spinal cord.
· Unlike other classes of analgesics, opioids have a very large titration range. The analgesic ceiling effect generally occurs only at extremely high doses of opioids.
· Opioids offer flexibility in dosing routes that can be customized to a patient’s needs.
· Doses can be given via oral, transdermal, sublingual, intravenous, rectal, subcutaneous, intrathecal, intraventricular, buccal, and epidural routes.
· Refer to Table 37-3 for commonly prescribed opioids and dosing.13
· Data comparing opioid efficacy are limited, and the results are largely equivocal. Opioid selection may be based on desired route of administration, availability, and individual patient tolerance for a given drug.
· Meperidine
o Meperidine is NOT recommended for treatment of pain because of limited efficacy and a very short duration of analgesia with significant euphoria. Historically, it has been a significant prescription drug of abuse.
o Its active metabolite normeperidine accumulates in renal failure and can lower the seizure threshold.
· Tramadol
o Tramadol is both an opioid agonist and a centrally acting nonopioid analgesic that acts on pain processing pathways.
o Dosing is 50 to 10 mg PO every 4 to 6 hours. Maximum daily dose is 400 mg/day.
o Side effects include flushing, headache, dizziness, insomnia, somnolence, nausea, vomiting, constipation, dyspepsia, and pruritus. Dose titration starting with 25 mg and gradually increasing can improve tolerance.
o Tramadol is metabolized by the liver and excreted largely by the kidneys. It is not dialyzable. It has an active metabolite that can lower the seizure threshold, particularly when taken in combination with some antidepressant medications. It should not be used in patients with known seizure disorders.
· Codeine
o Codeine is an opioid prodrug with modest antitussive effects.
o To exert analgesic effect, codeine must be metabolized to morphine by the liver. Up to 10% of the US population lacks the appropriate enzyme for codeine metabolism. In these patients, codeine will provide analgesia similar to acetaminophen, but with higher rates of constipation. Like morphine, its clearance is reduced in the setting of renal impairment.
· Morphine
o Morphine is often the first-line opioid given its safety profile, ease of use, availability, and physician experience with its use.
o Two active metabolites of morphine can accumulate in renal insufficiency, so alternate opioids may be considered for patients with renal impairment.
· Oxycodone
o While a single meta-analysis found pain control to be slightly better with morphine than with oxycodone, dry mouth and drowsiness were less prevalent with oxycodone.14
o Oxycodone has few renally cleared active metabolites.
· Hydromorphone
o Available data suggest no significant difference in analgesia or side effects between hydromorphone and other opioids.15
o Hydromorphone has few renally cleared active metabolites.
· Methadone
o Methadone is an opioid agonist as well as an N-methyl-D-aspartic acid antagonist, producing analgesia with additional adjuvant effects for neuropathic pain.
o The half-life of methadone is relatively long and varies significantly between patients. The duration of methadone’s analgesic effect is much shorter than its half-life.
o Methadone interacts with many common medications resulting in further pharmacokinetic variability.
o Methadone has similar efficacy to morphine for cancer pain with similar side effects in short-term studies. However, in long-term studies, methadone side effects were more pronounced.16 In addition, recent data suggest an increase in mortality in patients using methadone, and the Food and Drug Administration (FDA) has urged caution and careful titration of methadone in pain therapy.17
o Methadone can be a very useful drug for chronic pain, but it is best prescribed by physicians experienced with its use. Close follow-up during dose titration is essential.
· Fentanyl
o Fentanyl may cause less constipation than other opioids; however, the difference is likely to be small.18,19
o Transdermal fentanyl is best used for stable pain syndromes.
o Fentanyl has no renally cleared active metabolites.
o Fentanyl patch absorption requires skin adhesion and subcutaneous fat. Response is less predictable in patients with cachexia, fever, or diaphoresis.
· Alternative opioid formulations
o Opioid combination pills with acetaminophen or ibuprofen are available in a wide variety of doses, but dose titration is limited by the maximum daily dose of acetaminophen or ibuprofen. Commonly prescribed combination pills are presented in Table 37-4.
o Considerations for patients unable or unwilling to take oral analgesics.
§ Transdermal fentanyl is useful if pain is stable.
§ Extended-release formulations of any oral opioids must not be chewed or crushed. Special coatings on the tablets or granules slow the medication’s release; destroying the integrity of the coating can result in potentially fatal overdose.
§ Liquid formulations of short-acting opioids can be given at scheduled intervals to provide basal analgesia. For example, 10 mg liquid morphine sulfate every 6 hours as basal medication, with 5 mg liquid morphine every 4 hours as needed for breakthrough pain.
§ Kadian (morphine sulfate extended release) comes in a capsule that can be opened. The granules must not be crushed but may be sprinkled in water and administered via gastrostomy tube (≥16 French).
· Conversion between opioids
o Use caution when converting between opioids as equianalgesic doses are approximations only (refer to Table 37-5).
§ Calculate the 24-hour dose of the current drug.
§ Convert this drug to the equivalent dose of the desired new drug with the following equation:
§ Reduce dose by 25% to 35% of the calculated new drug equivalent dose to account for incomplete cross-tolerance between opioids.
§ Divide the calculated new 24-hour dose by the number of doses planned per day. For example, divide by 2 for twice daily OxyContin or by 4 for doses of oxycodone given every 6 hours.
§ If using a basal dose of analgesic, calculate breakthrough doses of the new drug as 5% to 15% of the total daily dose, given at a frequency based on drug half-life.
o Ensure that the patient has adequate doses of breakthrough analgesia available when converting between opioids.
o The basal analgesic dose is intentionally reduced during opioid conversion to avoid risks of oversedation and respiratory depression with incomplete opioid cross-tolerance. This means that a patient’s pain may initially be undertreated with the new basal dose.
o Short-acting opioids can be given as frequently as every 2 hours for breakthrough pain during opioid transitions to avoid pain crises in the setting of lowered basal analgesia.
o Patients consistently requiring more than 2 to 3 doses of breakthrough pain medication per day may require an increase in their basal dose.
o Conversion to/from fentanyl
§ Use Table 37-6 when converting between fentanyl transdermal patches and oral morphine.
§ Increase the dose of fentanyl patch on the basis of the amount of daily breakthrough opioid required.
§ Do not titrate patch dose more frequently than every 72 hours.
§ Patches may not be cut. The lowest dose fentanyl patch is 12.5 μg/hour.
§ Converting to the fentanyl patch: The fentanyl patch takes 8 to 12 hours to reach peak effect, so place the patch at the same time as the last dose of oral long-acting medication is given.
§ Discontinuing the fentanyl patch: Remove the patch and start the new extended-release opioid 12 hours later.
§ Short-acting oral opioids can be used as needed every 2 hours for breakthrough pain during transitions to and from fentanyl patches.
TABLE 37-3 Commonly Prescribed Opioidsa
aOpioids are generally administered intravenously only in the hospital setting, although occasionally they are given subcutaneously in the outpatient setting. This usually occurs in a home hospice setting, and dosing is equivalent to intravenous dosing. Intravenous administration of opioids will not be discussed in this outpatient care manual.
bPeak serum concentration of most short-acting oral morphine preparations occurs after 1 hour. Short-acting doses can be given as frequently as every 2 hours without stacking/overlapping doses. While relatively stable pain is appropriately treated with breakthrough doses every 4 hours as needed, out-of-control pain can be addressed by dosing short-acting opioids every 2 hours.
cInitial dosing of short-acting oral morphine for opioid-naïve patients is 5–10 mg every 4 hours as needed. For an opioid-naïve patient starting oral morphine, solution should be used, as short-acting tablets are only available in 15- and 30-mg formulations.
dDuragesic and fentanyl 12 μg/hour patches actually supply 12.5 μg/hour.
Drug information from Lexi-Comp Online Drug Database. 2015. http://www.lexi.com. Last accessed 1/12/15.
TABLE 37-4 Opioid Combination Preparations
APAP, acetaminophen; ES, extra strength; HP, high potency.
TABLE 37-5 Equianalgesic Opioid Doses
Drug information from Lexi-Comp Online Drug Database. 2015. http://www.lexi.com. Last Accessed August 3, 2014.
TABLE 37-6 Oral Morphine/Transdermal Fentanyl Conversions
Adjuvant Drugs for Opioid Side Effects
· Constipation
o Both pain relief and constipation are related to steady-state levels of opioids. All patients on opioids are at risk for constipation, and tolerance does not develop for this side effect.
o There is limited evidence as to the most appropriate bowel regimen, but most patients on chronic opioids will require more than one anticonstipation drug. The combination of a stool softener plus a stimulant laxativeis a reasonable starting point.
§ Docusate sodium is a detergent stool softener given in doses of 50 to 500 mg/day divided once to four times daily. Sennosides is a stimulant laxative given in doses of 8.6 to 51.6 mg/day divided two or three times daily (maximum dose 100 mg/day).
§ Docusate/sennosides combination tablets (50 mg/8.6 mg) are also available; however, it may be less expensive for the patient if docusate and sennosides are prescribed separately.
§ Encourage adequate fluid intake.
§ Lactulose 10 to 20 g/day (15 to 30 mL) can be added and titrated up to 40 g/day, if needed.
§ Polyethylene glycol is an osmotic agent that may also be added. Dosing is 17 g (about one heaping tablespoon) dissolved into 4 to 8 oz of water once daily. This agent has not been FDA approved for long-term use.
o Titrate up the daily bowel regimen if no bowel movement occurs for 2 to 3 days.
o If refractory constipation develops, rule out complete or partial bowel obstruction before advancing therapy.
o PO naloxone can also be helpful for refractory opioid-induced constipation.
§ The dose is 0.4 mg PO every 2 to 4 hours as needed.
§ There is little systemic absorption of PO naloxone, so oral dosing should not interfere with pain control. Monitor closely, however, for increased pain.
o Subcutaneous methylnaltrexone is useful for patients with opioid-induced constipation who cannot tolerate oral therapy. It is contraindicated in patients with partial or complete bowel obstruction. Dosing varies with patient weight.
· Sedation
o Sedation is common with initiation or up-titration of opioids; tolerance usually develops over 2 to 3 days.
o If sedation persists consider decreasing the basal opioid dose and using increased breakthrough doses when needed.
o Switching opioids may help, if sedation is refractory.
· Nausea
o There are two forms of nausea associated with opioids, early and late.
o Early onset nausea occurs within 15 to 30 minutes of drug administration, is related to changes in serum drug concentration and is more common with intravenous opioids. This type of nausea responds well to serotonin antagonists such as ondansetron 4 to 8 mg PO/IV or dopamine antagonists such as low-dose haloperidol (dose may be as low as 0.5 to 1 mg PO/IV; note, this use of haloperidol is not FDA approved).
o Nausea that occurs later in opioid therapy is usually due to insufficient treatment of constipation. This form of nausea responds to improved bowel regimen.
· Respiratory depression
o Respiratory depression can occur with opioid administration, and is seen more frequently with initiation or up-titration of therapy. Respiratory depression is usually preceded by sedation.
o Dosage should be started low and titrated up carefully in opioid-naïve patients.
o IV naloxone can be used for life-threatening respiratory depression. Opioid reversal can result in a pain crisis, so naloxone should be diluted and titrated to effect.
· Pruritus
o Pruritus occurs with opioid use due to opioid-induced histamine release.
o This side effect is classically associated with morphine and may be less pronounced with other opioids, such as hydromorphone or oxycodone.
o Antihistamines can be used as needed.
o Tolerance usually develops, but if persistent, consider switching opioids.
Adjuvants for Neuropathic Pain
· Adjuvant analgesics have synergistic effects when combined with opioid medications and have been underused in the treatment of cancer pain.20
· Some medications may require titration over days to weeks for maximal results.
· Addition of adjuvant analgesics, however, can confer great benefits: adjuvant analgesics have been shown to increase the therapeutic index of opioids and reduce opioid side effects.21
· Antidepressants
o One-third of patients with neuropathic pain achieve moderate or better pain relief with adjuvant therapy with tricyclic antidepressants (TCAs).
o Selective norepinephrine reuptake inhibitors (SNRIs), including duloxetine and venlafaxine, have demonstrated similar efficacy to TCAs for treatment of neuropathic pain.22 Duloxetine has also been approved for the treatment of diabetic neuropathy.20
o Effective analgesic dose is often lower and onset of effect earlier than when treating depression.6
· Anticonvulsants
o Gabapentin is frequently used to treat chronic neuropathic pain and there is strong evidence to support its use in the treatment of diabetic neuropathy, postherpetic neuralgia, and acute postoperative pain after craniotomy.20
§ Starting dose is generally 300 mg at bedtime. This may be titrated up to a maximum of 3,600 mg/day, given in divided doses every 8 hours.
§ Maximum dose is lower in patients with renal insufficiency.
§ Most patients will require at least 900 to 1,500 mg/day to achieve pain control.
§ Gabapentin can cause sedation, but this effect usually attenuates after 3 to 5 days. It is important to closely monitor for sedation especially when titrating gabapentin along with an opioid.
o Pregabalin is a newer anticonvulsant, with a mechanism of action, efficacy, and range of adverse effects similar to gabapentin. The dose range is 100 to 600 mg/day divided into 2 or 3 doses.
o Carbamazepine has some efficacy in neuropathic pain, such as trigeminal neuralgia and diabetic neuropathy.
o Lamotrigine has been used to treat trigeminal neuralgia, HIV neuropathy, and central poststroke pain. There are reports of good effect with the use of levetiracetam and oxcarbazepine in the treatment of chronic neuropathic pain. More studies are needed; the evidence is evolving.23
· Other adjuvants
o Local anesthetics such as lidocaine transdermal patches may be effective for some localized pain due to strains, sprains, or tumor invasion of tissue. In order to prevent systemic absorption, they should be applied to intact skin for no more than 12 hours/day.
o Steroids may be useful for patients with metastatic bone pain or nerve compression.20 They can increase appetite and help with nausea.
o Bisphosphonates can be helpful for refractory bone pain and for chronic regional pain syndrome.8,21
o Benzodiazepines and selective serotonin/norepinephrine reuptake inhibitors may decrease anxiety and thus help patients cope with chronic pain.
o Neuroleptics cannot be recommended for adjuvant pain therapy on the basis of current available data.24
Other Nonpharmacologic Therapies
· Psychotherapy, cognitive-behavioral therapy, mindfulness, and counseling can be useful adjuncts for patients with chronic pain.
· Physical and occupational therapy can help some patients increase functionality and independence.
· Acupuncture has also been used with success as a therapy in cancer-related pain.
· Massage may be helpful for some patients.
· Radiation therapy is indicated for cancer pain caused by metastatic disease to bone and brain and for radicular pain caused by tumors compressing neural structures.
· Transcutaneous electrical nerve stimulation is available for pain therapy, although there are currently insufficient data to support its use.25–27
REFERRAL
· If pain cannot be adequately controlled, referral to a pain specialist should be considered for more advanced medical management or specialized procedures.
· A full discussion of procedural interventions for pain syndromes is beyond the scope of this chapter.
· Available techniques include steroid injections, neurolytic blocks, and surgical procedures such as rhizotomy, cordotomy, and implantation of intrathecal or intraventricular opioid delivery systems.
MONITORING/FOLLOW-UP
· Treatment of pain is an iterative process; one of its most important components is close follow-up and frequent reevaluation of the therapeutic plan.
· If pain is not controlled, appropriate adjustments to the patient’s regimen should be made.
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