How Should Opioids Be Started and Titrated?

Overview of Opioid Pharmacology

The pharmacology of opioids dictates the way in which opioids are prescribed and administered. The administration of intravenous opioids is associated with the most rapid onset of analgesia. The time to peak plasma concentration and therefore peak effect of intravenous opioids can vary, although the general range is 5 to 30 minutes. The duration of effect is usually 3 to 4 hours—this is the basis for selection of 4 hours as the standard dosing interval for short-acting opioids (e.g., immediate-release morphine sulfate, oxycodone, or hydromorphone) for people without renal or hepatic impairment. Opioids are conjugated in the liver and excreted (approximately 90% to 95%) by the kidney.

How Do Renal and Hepatic Function Impact Opioid Pharmacology?

Morphine is metabolized in the liver to morphine-6-glucuronide and morphine-3-glucuronide, both of which are excreted by the kidneys. In the setting of renal failure, these metabolites can accumulate, resulting in a lowering of the seizure threshold. Morphine should therefore be used with caution with mild renal impairment and be avoided in the setting of renal failure. Opioid metabolism is generally impaired in the setting of liver disease, with an increase in oral bioavailability and an increase in elimination half-life. In the setting of severe liver disease, opioids should be used with caution, with a decrease in dose and increased (i.e., longer time between) dosing intervals. For a full discussion of opioid use for people with renal or hepatic dysfunction, see Chapter 4 .

Fentanyl and methadone have few active metabolites and are therefore likely to be safer than other opioids for the treatment of patients with renal or hepatic dysfunction. The most commonly available nonparenteral formulation of fentanyl in the United States is transdermal. As discussed later, transdermal fentanyl should be administered only to a patient who is opioid tolerant, and it should be avoided in patients for whom the opioid dose is being actively titrated. For an in-depth discussion of the use of methadone in treating patients with pain, see Chapter 5 .

Does Patient Age Impact Opioid Pharmacology?

Several changes in pharmacokinetics and pharmacodynamics occur with increasing age. Physiological decline in organ function (e.g., decreased glomerular filtration with increased age) and an increased volume of distribution as a result of relative increase in body fat content over skeletal muscle mass can affect the pharmacology of analgesics. Therefore the onset of action, rate of elimination, and half-life of these medications may be altered in older patients. Because of these changes, the prescribing philosophy should be “start low and go slow” (i.e., start at a low dose and increase with caution) when treating older patients with opioids. To be clear, however, older age is not a contraindication to opioid use.

Initial Approach to Assessing the Patient in Pain

The experience of pain is subjective, and therefore a patient’s report of pain is the gold standard for assessment. The first step in treating a patient is to perform a comprehensive pain assessment. The goal of the pain assessment is to begin to establish the factors summarized in Fig. 1.1 , which will determine the overall approach to pain and the specific regimen.

Nature of the pain: It is important to determine if pain is somatic, visceral, or neuropathic through both patient interview and physical exam. Somatic pain may be present in patients with bone disease or metastases, and may be clearly localized by the patient. It may be intermittent or constant, and described as aching, gnawing, or throbbing. For a description of approaches to bone pain, see Chapter 8 , and for consideration of radiotherapy for bone pain related to cancer, see Chapter 9 . Visceral pain is a result of pathology in the gastrointestinal, genitourinary, cardiovascular, or respiratory system and may be referred to other anatomic locations. It may be described as deep, squeezing, or colicky. Neuropathic pain is the result of damage to the nerves, and may be burning, tingling, or shocklike. It may be associated with allodynia on physical exam, with pain elicited by light touch. For a full description of evaluation and treatment of neuropathic pain, see Chapter 6 .

Causes of pain: It is important to establish a differential of contributing causes of pain, which may be multifactorial. As noted in the preceding section, this is to differentiate nociceptive from neuropathic contributions to pain, so that the therapeutic regimen can be appropriately tailored. Identifying the precise anatomic cause of the pain through correlating patient symptoms with any available imaging may be helpful to consider if modalities such as radiotherapy ( Chapter 9 ) or nerve blocks ( Chapter 14 ) may be useful. Assessing for existential or spiritual distress ( Chapter 75 ) and concurrent psychiatric conditions such as anxiety or depression ( Chapter 25, Chapter 26 ) is important to optimally address the contributing causes and appropriately mobilize a multidisciplinary approach to pain. Some specific illnesses have unique pain characteristics, such as mouth pain in head and neck cancer ( Chapter 49 ) and mucositis as a complication of treatment for hematologic malignancies Chapter 38 .

Anticipated course of pain: Understanding the anticipated course of the pain is useful to logistically approach choice of opioid or regimen. For example, if pain is anticipated to be severe for a brief period and then rapidly resolve, such as after a procedure or during radiation or chemotherapy, it may make more sense to use short-acting opioids to rapidly titrate the opioids to the level of pain, and then taper them. If pain is anticipated to continue for the duration of the patient’s life, it might make sense to consider a long-acting pain regimen such as transdermal fentanyl, methadone (see Chapter 5 ), or long-acting morphine, or to consider an intrathecal pump (see Chapter 13 ).

Assessing severity of pain and differentiating the patient in pain crisis: A variety of tools may be used for the assessment of pain severity, including numeric pain intensity rating scales (0 = no pain and 10 = worst possible pain) and verbal descriptor scales (mild, moderate, or severe). The numeric rating scale offers several advantages, including ease of administration and scoring, multiple response options, and no reported age-related difficulties in its use. For younger patients, the Faces Pain Scale may be more effective than verbal report. (For more information on treating pediatric patients, see Chapter 55 ). Clinicians should assess pain intensity regularly because this helps guide the initial approach to treatment, response to treatment, and need for further titration of medications.

The WHO first developed guidelines for the management of cancer pain in the mid-1990s, revised them in 2011 and 2012, and revised them again in 2018 in the context of balancing concerns for appropriate analgesia with concerns about the opioid crisis in the United States. The WHO recommends a stepwise approach to pain management, with choice of medication based on pain severity, using nonopioids (aspirin and acetaminophen) with or without an adjuvant (such as steroid, antidepressant, anticonvulsant, or bisphosphonate) for mild pain, an added opioid for mild to moderate pain, and higher doses of opioids such as morphine for moderate to severe pain. While this pain management ladder emphasizes that individuals with moderate or severe pain should not be initiated on a nonopioid or adjuvant alone, it does include nonopioids and adjuvants at every rung of the ladder. Notably, the use of combined opioid/nonopioid medications (such as that combining acetaminophen and oxycodone) is limited by the nonopioid component (e.g., in combination medications containing acetaminophen, the total acetaminophen dose for a healthy individual is less than 4 gm per 24 hours, and it may be lower in older patients or those with liver disease). Given these concerns, combination medications will not be further discussed in this chapter. Assessing pain severity is also important to identify those patients in pain crisis, or severe pain; the optimal approach to the patient in pain crisis will be described shortly. For outpatients presenting or calling with severe pain, the clinician should consider whether the patient would benefit from inpatient admission to ensure more rapid relief by titrating intravenous opioids as opposed to dose-finding with oral opioids in an outpatient setting.

Identifying the temporal pattern of pain: The approach to initial opioid dosing is also closely linked to the temporal pattern of pain. Pain may be constant, requiring long-acting opioids or around-the-clock dosing of opioids, or it may be intermittent. If intermittent pain occurs only with unusual activities, such as a daily physical therapy session, opioids may be used sparingly before and during the activity. If pain occurs intermittently but frequently, such as with swallowing or eating, opioids may be required both at lower levels around the clock and with additional doses before meals.

Opioid management for patients with renal or hepatic impairment: As noted earlier, end organ dysfunction impacts opioid pharmacokinetics. See Chapter 4 for a complete approach on how to consider changes in opioid dosing in patients with impaired renal or hepatic function.

Anticipating financial or logistical issues in obtaining opioids: Long-acting opioids in particular may be highly costly and subject to health insurance prior authorization procedures. In addition, obtaining large quantities of opioids or obtaining multiple opioid prescriptions in 1 month may be limited by insurance companies, pharmacy availability, and state opioid rules in light of the opioid epidemic (see Chapter 11 ). Therefore best practice includes identifying a prescribing pharmacy and working closely with the managing pharmacist to ensure that any opioid regimen requiring large doses, long-acting opioids, or unusual formulations (such as liquid formulas) be practically available and that any necessary prior authorization procedures be conducted before the patient needs the medication.

Considering the patient’s physical and cognitive ability to take medications: Patients who are unable to swallow medications have multiple options, including liquid formulations (especially at low doses), fentanyl patches, and intravenous or subcutaneous formulations (especially in inpatient or facility settings). Patients who rely on family caregivers to manage medications may benefit from long-acting medications in a form that may be dosed 2 or 3 times daily (such as long-acting morphine or oxycodone; or methadone), or fentanyl patches. These logistic complexities are important to be aware of when selecting an initial opioid.

Considering the patient’s risk of opioid misuse: All prescribers initiating opioid treatment to a patient, whether or not that patient has been previously prescribed opioids, need to be mindful of the patient’s risk of opioid misuse. For a nuanced discussion of these considerations, see Chapter 12 . Safe treatment of pain in patients with or at risk for opioid use disorder is a complex topic with multiple research gaps. All patients should be screened with a brief opioid misuse risk screening tool, such as the CAGE-AID. In addition, if available, the state opioid prescription registry should be checked to assess for any unanticipated prior opioid prescriptions. Even for a patient in pain crisis, as soon as the crisis is appropriately managed, the clinician should screen for risk of opioid misuse. This step is critical to determine a safe opioid prescription plan for the patient and to appropriately coordinate with addiction psychiatry if necessary. Frequently checking with state prescription monitoring databases is also useful to corroborate patient descriptions of prior prescriptions and to ensure that patients are not being prescribed opioids from other sources.

Selecting an Initial Opioid