Shopping Cart

Introduction

Special populations, which include children, elderly adults, pregnant women, and those with complex comorbid conditions, are often excluded from clinical trials.¹ The United States Food and Drug Administration (FDA) has estimated that nearly 40% of the US population is composed of pediatric geriatric individuals and pregnant individuals.² These populations frequently have altered pharmacokinetic profiles that can cause variability in the effectiveness of medications.¹ Another setting that requires special consideration with regard to medication prescribing is palliative care, which focuses on symptom management and frequently involves patients with advanced cancer. Palliative care patients may require special dosing and additional considerations when medications are prescribed. These patients may also have multiple comorbid conditions that can affect drug response. Additionally, intrinsic patient factors, such as age, weight, comorbid conditions, genetic variance, and renal or hepatic impairment, can lead to an increase or decrease in drug exposure compared to what would be expected in the general population.³

Acute pain from injury or surgery has been estimated to affect 25 million patients in the United States per year; an additional third of the population will experience severe chronic pain at some point during their lifetime.⁴ Young children and older adults are more likely to receive inadequate treatment for pain, especially when they are unable to verbally communicate to describe their pain to a health care provider. Overall, women are more likely to be affected by pain disorders than men. In particular, pregnant women are usually excluded from clinical trials and much is unknown about the safety of pain management in this population.⁵ Therefore, health care providers may lack education and feel uncomfortable with managing pain in pregnant women. Patients who are receiving palliative care often have severe, complex, and life-threatening diseases and require specialized pain management in order to palliate, or lessen, their pain.⁴ This module will focus on management of pain in special populations, as there are a number of physiologic changes in these populations that may affect an individual patient’s response.

Pregnancy/postpartum/breastfeeding

Pregnancy is associated with significant physiological alterations that can have an impact on drug exposure.⁶ The presence of nausea and vomiting in pregnancy can decrease drug absorption, and movement through the gastrointestinal tract is often slowed. Distribution of drugs is increased due to weight gain and fat deposition, increased plasma volume, and decreased plasma protein concentration. Effects on hepatic enzymes are variable, leading to either an increased or decreased exposure to hepatically metabolized drugs. Blood flow to the liver and kidneys is also increased, leading to higher clearance of a number of drugs from the body. In addition to these considerations, the possible effects of transmission of a given drug from mother to fetus must be considered. After birth, these physiologic changes slowly return to normal. However, postpartum women who breastfeed must consider the potential for transmission of drugs into the breastmilk and the potential impact on the infant. Pain can impact women throughout all stages of pregnancy, postpartum, and while breastfeeding.⁷ Treatment of pain in these populations can be challenging due to a lack of data overall to guide proper management.

Pregnancy

Pain can occur as the result of physiologic changes that take place during the course of pregnancy, or from preexisting pain conditions that are worsened during pregnancy.⁷ Some examples of common types of pain that occur during pregnancy include lower back, joint, pelvic/abdominal, and neuropathic pain. Expansion of the uterus can cause abdominal and back pain; pregnancy-related weight gain can place additional strain on the back. Furthermore, loosening of ligaments during pregnancy can contribute to the development of back and pelvic pain. Joint pain can occur in women with preexisting inflammatory conditions that are exacerbated during pregnancy. Nerve pain is also common, with up to 35% of pregnant women experiencing carpel tunnel syndrome and other women experiencing pain due to nerve compression.

Since pregnant women are often excluded from clinical trials, much is unknown about the safety of pain medications in this population.⁷ Therefore, nonpharmacologic strategies, such as those described in Table 1, are utilized first-line for the management of pain. Education is a key component to the nonpharmacologic management of pain in pregnant women. Postural modifications and rest can help to reduce back pain initially; physical therapy is also an option for pain that persists despite these measures. Manual manipulation strategies, including acupuncture/acupressure and massage, should be avoided in the first trimester since they can stimulate uterine contractions. These interventions can be utilized after the first trimester in pregnancies that are not considered high-risk, but should only be performed by experienced therapists. Water therapy should also be used with caution throughout pregnancy, and hot tubs should be avoided. Chiropractic care should also be used with caution in the first and third trimesters to avoid placing pressure on the abdomen and back, respectively. Other methods, including use of a transcutaneous electrical nerve stimulation (TENS) unit, cognitive behavioral therapy, and biofeedback are safe throughout pregnancy.

When these methods are unsuccessful and pharmacologic agents must be used to manage pain, acetaminophen is recommended first-line.⁷ Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are generally not recommended and should be avoided during the third trimester since they can cause premature closure of the ductus arteriosus in the fetus. Some studies have also shown a potential risk for spontaneous abortion in earlier trimesters with NSAID use, although data are conflicting. When pain is severe and uncontrolled, even with these agents, opioids may be considered. Short-term use of opioids has been shown to be generally safe; however, chronic use of these agents must be used with caution in order to prevent neonatal opioid withdrawal syndrome (NOWS). Of note, codeine should not be used in the first trimester as it has been associated with birth defects.

NOWS, also called neonatal abstinence syndrome, refers to the presence of withdrawal symptoms in a neonate after birth, as a result of opioid use in the mother during pregnancy.¹⁰ This disorder can occur from illicit or legal opioid use, and it is estimated that approximately 10,000 infants are affected by NOWS per year. The presence of central nervous system reactions (eg, vomiting, increased muscle tone, decreased sleep) as well as autonomic nervous system signs (eg, sweating, increased respiratory rate, nasal congestion) are indicative of NOWS. These signs typically occur within 24 to 72 hours after birth. A number of scoring-based assessment tools are available to determine the severity of neonatal opioid withdrawal.¹¹ Nonpharmacologic treatment methods, such as providing a dark environment with minimal stimulation, decreasing stress by holding, cuddling, or rocking the infant, and swaddling are generally preferred. When signs of NOWS are moderate to severe despite nonpharmacologic management, pharmacologic treatment is warranted. Definitive treatment recommendations have not been established; opioids, barbiturates, benzodiazepines, clonidine, and phenothiazines have been used to control symptoms in practice, although opioids are the most common initial treatment strategy. Gradual weaning from these agents should occur once the infant responds to treatment, as evidenced by a reduction in symptoms of withdrawal.

Postpartum/breastfeeding

The American College of Obstetricians and Gynecologists (ACOG) provides specific guidance on the management of pain in the postpartum period, nothing that uncontrolled pain can lead to difficulty caring for an infant, postpartum depression, development of persistent pain, and a risk for increased opioid use.¹² In the immediate period after delivery, sources of pain can vary depending on the mode of birth. After vaginal birth, women may experience pain due to breast engorgement, contractions of the uterus, and tears to the perineal region that occur during labor. Cesarean delivery is also associated with postoperative incisional pain. Postpartum women may also experience pain due to chronic pain conditions or other sources of acute pain unrelated to birth.

More than 80% of postpartum women begin breastfeeding after birth, which is an important consideration when determining how best to manage pain in this population.¹² Nonpharmacologic measures may be effective for the management of certain sources of pain. For example, ACOG recommends that women with pain due to breast engorgement apply cold packs or breastfeed more frequently. Cold or ice packs may also be used to numb the perineum and reduce inflammation. Postpartum uterine cramping can be lessened by application of heating pads to the abdomen. Nonpharmacologic topical agents, such as lanolin, can be applied to relieve pain associated with breastfeeding. Topical agents, including anesthetics, can also reduce perineal pain.

Per ACOG, when nonpharmacologic measures are not sufficient to manage pain, a multimodal, stepwise approach to pain management should be utilized following the recommendations of the World Health Organization’s (WHO) stepwise ladder for analgesia.¹² Following this strategy, initial management consists of nonopioid analgesics including acetaminophen or NSAIDs. ACOG and the Academy of Breastfeeding Medicine (ABM) recommend ibuprofen first-line for pharmacologic treatment of pain in breastfeeding women since it has a short half-life and minimal transmission into breastmilk.^12,13 Ketorolac (either oral or injectable) is also an option for the treatment of moderate pain as long as it is administered only within the first few days after birth before milk production increases. Additionally, ABM suggests that short-term use of celecoxib and naproxen are safe in breastfeeding mothers.¹³ Although they are generally recommended first-line, NSAIDs should not be used by mothers with infants who have ductal-dependent cardiac lesions.

When NSAIDs alone do not alleviate pain, a multimodal approach may include addition of acetaminophen and/or a mild opioid such as hydrocodone, oxycodone, or oral morphine (or combination products that feature one of these opioids in combination with acetaminophen).¹² Codeine and tramadol, as well as hydrocodone and oxycodone to a lesser extent, may produce higher than expected blood concentrations in women with genetic abnormalities of the hepatic enzyme cytochrome P450 (CYP) 2D6.^12,13 Codeine and tramadol should be avoided in breastfeeding mothers, if possible, because of this potential.^12-14 Infants should also be monitored for sedation when any opioid is given to a breastfeeding mother.^12,13 Additionally, if opioids are used, lower doses should be employed so that the mother can be more mobile and better able to care for the infant; lower doses also minimize transmission of opioids into breastmilk.¹² Scheduled delivery may be preferable to as-needed delivery in order to provide consistent pain control while reducing overall opioid requirements. If mild opioids are ineffective, stronger pain management may be required with intravenous morphine, hydromorphone, and fentanyl. Use of stronger opioids should be minimized as much as possible, and women should be transitioned back to milder opioids as soon as feasible. Gabapentin may also be considered as part of a multimodal pain treatment strategy or for treatment of neuropathic pain. Although limited data are available, gabapentin appears to be safe for breastfeeding mothers to use on a short-term basis.^12,13 ABM recommends several resources to determine the safety of drugs during lactation: LactMed, E-Lactancia, Infant Risk Center, Breastfeeding and Human Lactation Study Center, Mother to Baby, and Motherisk.¹³

Pediatrics

Pediatric subpopulations, which include neonates, infants, children, and adolescents, have distinct characteristics that affect drug responsiveness.³ These subpopulations are differentiated by age after birth; depending on age, a pediatric patient can be defined as: neonate (0 to 30 days after birth), infant (1 month to 1 year), child (1 year to 12 years), or adolescent (> 12 years to 21 years of age). Pediatric drug absorption is affected by factors such as gastric pH and emptying time, functionality of the biliary tract, and intestinal transit time. Neonates have higher pH values in the stomach and functioning of the gastrointestinal tract is altered while it continues to develop. As neonates grow older, gastrointestinal functioning becomes more similar to what would be expected in adults. The distribution of drugs within the body is also affected by age-related differences within the pediatric population. Alterations in the concentration of plasma proteins and body composition, including proportions of fat and water, can have a significant impact on drug effects. Neonates generally have increased water volume, low concentrations of plasma proteins, and less body fat, thus resulting in altered plasma drug concentrations. Neonates also have a reduced ability to metabolize drugs due to a reduced number of hepatic enzymes. Infants and young children, however, tend to have increased hepatic metabolism compared to neonates and adults. Drug excretion is also variable, with reduced excretion in neonates that rapidly increases by the age of 1 year.

Pediatric patients are just as susceptible to experiencing pain as the rest of the population; however, it may be difficult to assess pain in younger patients, especially those that are very young and unable to verbally communicate.¹⁵ In infants and nonverbal children who are unable to report on the location or severity of their pain, there are several observational assessment tools that can be utilized. Examples of observational tools used to facilitate pain assessment in very young children include the Revised Face, Legs, Activity, Cry, Consolability (r-FLACC) tool, the Non-Communicating Children’s Pain Checklist-Postoperative Version (NCCPC-PV), the Nursing Assessment of Pain Intensity (NAPI), the Paediatric Pain Profile (PPP), and the Individualized Numeric Rating Scale (INRS). These tools are generally used by assigning points to various observable actions that may indicate pain in a young child. Behaviors that are often assessed include vocalizations such as crying, facial expression, ability to be consoled, and level of movement. For example, the r-FLACC tool assigns 0 points for a child with normal or relaxed leg positioning or 2 points for a child that is kicking or drawing up their legs with constant jerking or tremors. While these tools can be helpful in determining whether a young child may be in pain, children as young as 3 years of age are capable of quantifying their level of pain using visual analog scales containing a series of faces that indicate the level of pain they are experiencing. Children between 8 and 11 years of age often report their level of pain using visual analog tools that rate pain severity on a numeric scale. Adolescents are able to provide the most comprehensive description of pain without the need for an additional assessment tool.

Several nonpharmacologic measures may be effective at managing pain without the need for prescription medications in this population.¹⁵ Physical measures, including manual massage of the painful area, application of heat or cold, and acupuncture may be helpful. Exercise, biofeedback, and art and play therapy may assist in pain management from a behavioral approach. Finally, cognitive measures, including psychotherapy, distraction from pain, and hypnosis may also assist when managing pain in children. These measures have been found to be especially helpful to reduce stress in children that require invasive procedures. Table 1 provides a description of many of these strategies.

Existing guidelines on pain management in pediatric patients are dated; recommendations have not changed in recent years. Guidelines on pain management in pediatric patients were last published by the American Academy of Pediatrics in 2001, and by the WHO in 2012, although an update to the WHO guideline is pending.^16,17 Similar to pain management in other populations, a stepwise approach should be utilized with oral, nonopioid analgesics (acetaminophen and ibuprofen) used for milder pain and opioids for more severe pain. As noted in the WHO guideline, children less than 3 months of age should only receive acetaminophen. Children > 3 months may be given either acetaminophen or ibuprofen; the guideline notes that other NSAIDs have not been well-studied in pediatric patients, although ketoprofen, naproxen, indomethacin, and ketorolac have been used.¹⁵ Aspirin is generally not recommended, especially in children younger than 12 years, due to the risk for development of Reye’s syndrome.

When pain progresses and is moderate to severe, opioids are recommended.¹⁷ Morphine is recommended first-line by guidelines for use in children due to its relative efficacy, safety, affordability, and its availability in multiple dosage forms. Other commonly used agents include hydromorphone, oxycodone, and hydrocodone.¹⁵ Oral formulations are preferable, if tolerated, although intravenous opioids may be necessary for severe pain. Short-acting agents should be used to treat acute pain. Extended-release preparations (eg, oxycodone extended-release or transdermal fentanyl) or agents with long half-lives (eg, methadone) are potentially appropriate for chronic, severe pain. Codeine and tramadol should be avoided in children younger than 12 years old and used with caution in children older than 12 years due to the risk for overdose in children who are rapid metabolizers. A summary of initial dosing recommendations from the WHO for commonly used analgesic agents in children is provided in Table 2.¹⁷ The higher end of the listed dosing ranges in children can also be used to establish doses in adolescents.

Geriatrics

The US Census Bureau predicts that by the year 2034, there will be more people in the United States aged ≥ 65 years than there are children.¹⁹ However, older adults are often excluded from clinical trials since they may have various comorbid conditions for which multiple medications are prescribed.^3,20 The elderly experience gastrointestinal changes that may affect absorption, including increased stomach pH, delayed stomach emptying and blood flow/movement through the gastrointestinal tract, and decreased surface area for absorption. Age-related changes in body composition and concentration of plasma proteins also impact drug distribution. Older adults generally have a lower proportion of lean body mass, decreased water volume, and an increase in body fat, which can affect the distribution of hydrophilic and lipophilic medications. Hepatic metabolism of drugs may also be decreased in older adults; both the size of the liver and hepatic blood flow are reduced with aging. Renal function is also known to decline with aging; this decreases clearance of drugs that are renally eliminated.

In addition to pharmacokinetic and physiological differences in older adults, these patients may also understate the level of pain that they are experiencing.²⁰ Therefore, it is important that screening and assessment of pain is thorough and conducted on a regular basis. This may be particularly challenging in patients with cognitive decline, dementia, or in those that are nonverbal. In these patients, behavioral cues are used to assess pain, similar to those used in nonverbal young children.²¹ Several different scales are available to assist in patient assessment of pain. These scales consider facial expression, vocalizations, physical movement, changes in activity patterns or interactions with others, and alterations in mental status. Once pain is established, nonpharmacologic methods for pain management, such as those described in Table 1, can be an effective early management strategy.

When pharmacologic treatment is necessary, the American Geriatrics Society recommends acetaminophen first-line for mild pain in patients without hepatic disease.²⁰ NSAIDs place older patients at risk for gastrointestinal bleeding, cardiovascular toxicity, issues with blood pressure control, difficulty managing heart failure, and adverse renal effects; thus, they should be used cautiously and patients should be monitored for these adverse effects. However, NSAIDs may be preferable to acetaminophen for chronic inflammatory pain, osteoarthritis pain, and lower back pain. If a patient is at risk for gastrointestinal bleeding with a NSAID, a cyclooxygenase-2 selective NSAID (eg, celecoxib), topical NSAID, or combination of an NSAID with a gastroprotective agent can be used to reduce risk. NSAIDs should only be used for short periods of time, if indicated, and the choice of agent should depend on the patient’s individual risk factors for gastrointestinal, cardiovascular, or other risks.²¹ Topical agents including NSAIDs, capsaicin, and lidocaine can also be used to alleviate pain without systemic effects.

An opioid may be considered in patients with moderate-to-severe pain, functional impairment due to pain, or reduced quality of life as a result of pain.²¹ The choice of opioid agent should be made based on patient-specific factors including preferred route of administration, pharmacokinetic parameters of the drug including onset and duration of action, drug interactions, comorbidities, and adverse effects. Generally acceptable opioids include morphine, oxycodone, buprenorphine, hydromorphone, and fentanyl. Hydromorphone, meperidine, morphine, codeine, and oxycodone are renally cleared; if prescribed, conservative doses should be given to patients with renal impairment to avoid toxicity from accumulation of metabolites. Since older patients are more likely to experience adverse effects from drugs and often have some degree of renal impairment, initial dosing for any opioid should start at the low end of the dosing range, and titration should be conservative. Older patients with chronic opioid use at risk of overdose should also be considered for naloxone distribution and education.²² Adjunctive nonopioid agents may be helpful, especially for neuropathic pain, and may allow for lower opioid doses if given concomitantly. For neuropathic pain, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and certain anticonvulsants may be useful. However, many of the agents in these classes require renal adjustment and may cause sedation, thus increasing a given patient’s risk of falls. Muscle relaxants should be avoided in older adults as they may cause drowsiness, anticholinergic effects, and weakness.

Palliative care

The WHO defines palliative care as a means to improve quality of life for patients of all ages with serious, life-threatening diseases, and for their families, by assessing and treating pain and other symptoms and providing physical, psychosocial, and spiritual support to relieve suffering.²³ Symptom management and other palliative care services can be provided in conjunction with life-prolonging treatments, contrary to hospice care, a subset of palliative care that is available to patients who decide to discontinue curative treatment.²⁴ As the condition of a patient receiving palliative care progresses and becomes more severe, pain is often controlled with opioids.²⁵ Untreated pain can be common at the end of life, and health care providers can contribute to this issue out of fear of hastening death by providing high doses of opioids. While administering opioids to lessen pain in patients near the end of life is an important and legal strategy to relieve suffering, providers may be unsure where the line is drawn between providing pain relief, physician-assisted dying, and voluntary active euthanasia. This misunderstanding frequently leads to under dosing of pain medications due to fear of hastening death and associated potential legal implications. However, it is legal to aggressively treat pain in a patient suffering from a terminal disease, even if it is to the point of hastening death; in fact, providers could be at risk for litigation if they do not provide appropriate pain management to patients at the end of life.

As stated previously, opioids are commonly utilized to treat pain in patients receiving palliative care, especially as they near the end of their life.²⁶ Opioids, such as morphine, can provide additional relief to patients with breathing difficulties. Patients receiving palliative care for severe diseases other than cancer (eg, advanced heart failure) may be opioid-naïve. Thus, low starting doses of less potent opioids, such as morphine, should be utilized and titrated up as needed to control symptoms of pain and dyspnea. Short-acting agents that can be administered orally are preferred, since extended-release formulations may be more likely to accumulate, especially in patients with multiple comorbidities and declining renal function. Scheduled opioids are preferred over as-needed orders to ensure adequate pain control, since many patients with advanced disease states may be unable to request pain medication.

Patients with cancer comprise a significant portion of the palliative care population, and frequently experience pain. In fact, one systematic review estimated that more than 50% of patients with cancer at any stage reported experiencing pain.²⁷ Other studies have shown that pain becomes progressively worse as cancer becomes more advanced, with nearly one-third of patients with advanced cancer rating their pain as moderate to severe. Detailed guidelines providing recommendations related to treatment of pain in oncology patients are available from the WHO and the National Comprehensive Cancer Network (NCCN).^28,29 These guidelines generally follow recommendations from the WHO’s stepwise ladder for relief of pain in adults with cancer.³⁰ The pain relief ladder, which has been described in other areas of this module as a general strategy for approaching pain relief, recommends administering non-opioid analgesics such as acetaminophen for initial pain management, then adding on mild opioids for mild-to-moderate pain, followed by strong opioids for severe pain, until pain relief is achieved. Adjuvant drugs, including steroids, antidepressants, and anticonvulsants can be added at any stage of the ladder to provide additional pain relief.

The NCCN guidelines provide recommendations for adjuvant treatment options based on the origin of pain.²⁸ When pain is the result of mucositis, pharyngitis, or esophagitis, gabapentin, cryotherapy, or topical anesthetics are recommended. Bone pain can generally be treated with NSAIDs, acetaminophen, or steroids; bisphosphonates and other bone-modifying drugs can also be considered. If pain is related to bowel obstruction, metoclopramide or corticosteroids may be utilized for medical management and other strategies are suggested for palliation. Antidepressants (eg, tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors), anticonvulsants (eg, gabapentin or pregabalin), or topical agents (eg, lidocaine patches) are recommended for neuropathic pain, and corticosteroids may be helpful when managing pain related to compressed or inflamed nerves. Antidepressants are typically dosed lower when used to treat neuropathic pain than doses necessary to treat depression.

When treatment with opioids is warranted, the guidelines do not specify a preferred opioid. Meperidine is not recommended for pain management in patients with cancer due to its metabolite, normeperidine, which is toxic to the central nervous system. The guidelines also recommend against use of mixed opioid agonists/antagonists (eg, pentazocine, nalbuphine, and butorphanol), since they have limited usefulness when treating cancer-related pain. When prescribing opioids, the lowest possible dose should be administered to allow the patient appropriate pain relief, the ability to function, and limited adverse effects.

Additional considerations

In addition to the information described above, the following potential factors should be considered when determining how best to care for a patient with pain that falls into one of these special populations.

Dysphagia

Generally, guidelines recommend administration of pain medications by the oral route; however, children, elderly adults, and patients receiving palliative care may be unable to swallow solid oral dosage forms for various reasons. Pediatric guidelines from the WHO recommend that pain medications be given via whichever route is least painful and most effective, and recommend avoidance of intramuscular administration since it is more painful than other routes.¹⁷ Liquid solutions or suspensions are useful alternatives when children are not able to swallow tablets. Similarly, older patients may have various reasons why they are unable to swallow. Guidelines from the American Geriatric Society suggest that transdermal, rectal, and transmucosal oral formulations may be useful in these patients. The guidelines also state that subcutaneous and intramuscular formulations are not preferred since these routes may have variable absorption and faster offset compared to oral formulations.²⁰ Patients receiving palliative care, especially those with advanced disease nearing the end of life, may be unable to swallow oral medications due to weakness or excessive sedation.²⁶ If a palliative care patient has a gastrostomy tube, liquid preparations or crushed tablets may be able to be administered through the tube. Other formulations that may be useful are subcutaneous, intravenous, transdermal, nasal or oral transmucosal, and rectal formulations. Table 3 below describes commonly used pain medications that are available in alternative dosage forms to tablets or capsules.

Renal/hepatic impairment

Renal and hepatic function must be taken into account when determining which pain medication will be the best option for a given patient. Special populations, including children, older adults, and palliative care patients may have altered renal and hepatic functioning. Some of the more commonly utilized agents to treat pain in these populations require adjustment for renal or hepatic impairment. Acetaminophen should be used with caution in patients with hepatic impairment and avoided altogether when hepatic dysfunction is severe.³¹ Older adults who are at risk for hepatotoxicity and patients with chronic liver disease may benefit from a reduced maximum daily dose of 2 grams of acetaminophen. NSAIDs should be avoided in patients with advanced liver disease. In general, opioids should be used with caution in patients with hepatic impairment, since many of them are metabolized in the liver. Morphine, oxycodone, and hydromorphone may accumulate in patients with hepatic impairment and should be initiated with doses at the low end of the dosing range. Codeine and tramadol require hepatic metabolism to convert to their active metabolites, and may be less effective in patients with advanced liver disease. Hepatic clearance of meperidine is extensive, thus, meperidine should not be used in patients with advanced liver disease. Fentanyl is considered safe in patients with mild to moderate hepatic impairment; short-term administration of methadone has also been found to be safe in patients with advanced liver disease. Acetaminophen is a safe, nonopioid option to prescribe in patients with advanced renal disease or those receiving hemodialysis since its main mode of metabolism is hepatic.^32,33 NSAIDs are generally not recommended for the treatment of chronic pain in patients with renal impairment, although they may be used for short-term pain relief with appropriate monitoring for adverse effects. Otherwise, patients with mild-to-moderate renal impairment are eligible to receive most other commonly prescribed pharmaceutical agents for the treatment of pain.³² Meperidine, morphine, codeine, and tramadol have active metabolites that are renally cleared; use of these agents should be avoided in patients with severe renal impairment to avoid accumulation of metabolites. Morphine, hydromorphone, and oxycodone are renally cleared, thus, dosing of these agents should be conservative in patients with renal impairment. Buprenorphine and fentanyl are mainly metabolized in the liver, and 80% of methadone is excreted in the feces; these agents are generally safer options to use in patients with renal impairment. In patients receiving hemodialysis, ideal pain management involves use of agents that are mainly cleared by non-renal mechanisms and those with characteristics that prevent removal during dialysis (eg, high molecular weight and protein binding, low water solubility, greater volume of distribution).^33,34 Morphine, codeine, and hydrocodone should generally be avoided in patients on hemodialysis; however, tramadol, hydromorphone, oxycodone, methadone, buprenorphine, and fentanyl have been used with success.

Genetic polymorphisms

Since opioids are extensively metabolized in the liver, genetic polymorphisms in the CYP enzymes can lead to altered drug levels.³⁵ One important polymorphism that has previously been described in this module involves variations in the CYP2D6 enzyme, which is involved in the metabolism of codeine, hydrocodone, oxycodone, and tramadol. Variations in this enzyme that result in loss of function variants may result in poor metabolizers of these drugs, whereas patients with ≥ 3 normal function variants are considered to be ultrarapid metabolizers. Codeine and tramadol are primarily metabolized by CYP2D6 to their active metabolite; therefore, poor metabolizers are unlikely to benefit from treatment with these agents and ultrarapid metabolizers are more likely to achieve supratherapeutic levels of these drugs after metabolism. As a result of these risks, the FDA has determined that both of these drugs are contraindicated for use in children due to the risk for ultrarapid metabolism leading to respiratory depression and death; breastfeeding women should also avoid using these agents due to potential adverse effects in the breastfed infant.¹⁴ The current body of literature is insufficient to definitively describe the direct effects of other genetic polymorphisms on other opioids, although existing evidence does indicate that genetic variation leads to differences in analgesia when these drugs are used.³⁵

Hydrocodone, oxycodone, tramadol, and fentanyl are metabolized by the CYP3A4 (hydrocodone, oxycodone, tramadol, and fentanyl) and/or CYP3A5 (oxycodone, fentanyl) enzymes.³⁵ While it is likely that genetic variations in these enzymes affect metabolism of these agents much like the effects seen with CYP2D6, limited data are currently available. Phase II hepatic enzymes that are involved in the metabolism of certain opioids and are also likely affected by genetic variation include UGT2B7 and UGT1A1. Pharmacodynamic-related genes such as OPRM1, ABCB1, and COMT can also be affected by genetic polymorphisms. The OPRM1 gene codes for the mu opioid receptors, thus, genetic variability of this gene can affect the level of analgesia obtained from a given opioid. For example, the G variant allele of the OPRM1 gene, resulting in a GG genotype rather than an AA genotype, has been shown in studies to result in reduced pain relief from morphine necessitating higher daily dosages compared to patients with the AA genotype. While much is still unknown regarding the potential impact of genetic variability on pain management, future studies will elucidate how pharmacogenetic testing can be applied in practice to provide optimal pain management.

Sleep disorders

Sleep disorders are common among patients with pain.³⁶ Uncontrolled pain can cause disturbances in sleep; however, inadequate sleep can also contribute to increased pain severity. Patients treated with opioids for pain with concomitant sleep disorders are at risk for adverse outcomes related to sleep-disordered breathing (also known as sleep apnea), a condition that involves multiple pauses in breathing during sleep, reducing oxygen delivery to the brain and heart. Since opioids have a known potential to cause respiratory depression, these agents can worsen the hypoxemic effects of sleep-disordered breathing. Nonpharmacologic management strategies, such as providing education about sleep hygiene, cognitive behavioral therapy, exercise, biofeedback, or use of TENS devices can be utilized to provide alternate sources of pain relief. If pharmacologic treatment is needed in these patients, use of nonopioid analgesics or lower opioid dosages should be employed to limit this risk among patients with sleep disorders.

Conclusion

A special population often refers to a group of patients with unique physiologic or pharmacokinetic features that can lead to variable effectiveness of medications compared to what would be expected in the general population. As such, special populations are often excluded from clinical trials. Examples of special populations include women who are pregnant, postpartum, or breastfeeding, pediatric patients including neonates, infants, children, and adolescents, older adults, and palliative care patients. When managing pain in special populations, nonpharmacologic measures should be used first-line in an effort to manage pain while avoiding adverse effects that may be associated with pharmacologic agents. When nonpharmacologic measures are insufficient to manage pain, a stepwise approach to pain management is generally recommended by first trialing nonopioid agents such as acetaminophen or NSAIDS, then using mild opioids for moderate pain, and finally, using strong opioids for the most severe pain. Adjunctive agents can also be helpful to reduce neuropathic pain and reduce the dose of opioids. Pharmacologic management may need to be adjusted in patients with difficulty swallowing, renal or hepatic impairment, genetic polymorphisms, and concurrent sleep disorders.

References

1. Grimsrud KN, Sherwin CM, Constance JE, et al. Special population considerations and regulatory affairs for clinical research. Clin Res Regul Aff. 2015;32(2):47-56.
2. Owen RP. FDA’s clinical investigator course: clinical discussion of specific populations. Food and Drug Administration website. https://www.fda.gov/media/84964/download. Accessed April 27, 2020.
3. Lau S, Cheung LK, Chow D. Application of pharmaco­kinetics to specific populations: geriatric, obese, and pediatric patients. In: Shargel L, Yu AC. eds.Applied Biopharmaceutics & Pharmacokinetics, 7e.New York, NY: McGraw-Hill Education; 2016.
4. Herndon CM, Ray JB, Kominek CM. Pain management. In. Pharmacotherapy: A Pathophysiologic Approach, 11e. New York, NY: McGraw-Hill Education; 2020.
5. Ray-Griffith SL, Wendel MP, Stowe ZN, Magann EF. Chronic pain during pregnancy: a review of the literature. Int J Womens Health. 2018;10:153-164.
6. Kazma JM, van den Anker J, Allegaert K, Dallmann A, Ahmadzia HK. Anatomical and physiological alterations of pregnancy. J Pharmacokinet Pharmacodyn. 2020.
7. Shah S, Banh ET, Koury K, Bhatia G, Nandi R, Gulur P. Pain management in pregnancy: multimodal approaches. Pain Res Treat. 2015;2015:987483.
8. WHO cancer pain ladder for adults. World Health Organization website. https://www.who.int/cancer/palliative/painladder/en/. Accessed April 27, 2020.
9. Hamilton JP, Goldberg E, Chopra S. Management of pain in patients with advanced chronic liver disease or cirrhosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 27, 2020.
10. Davison SN. Management of chronic pain in advanced chronic kidney disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 27, 2020.
11. Raina R, Krishnappa V, Gupta M. Management of pain in end-stage renal disease patients: short review. Hemodial Int. 2018;22(3):290-296.
12. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28(5):497-504.
13. Owusu OA, Hamadeh I, Smith M. Review of opioid pharmacogenetics and considerations for pain management. Pharmacotherapy. 2017;37(9):1105-1121.
14. Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. Prog Neuropsychopharmacol Biol Psychiatry. 2018;87(Pt B):234-244.

Back to Top