Opioid Rotation: Mechanisms, Concepts, and Benefits

The last few decades have witnessed a surging interest in pain assessment and management. Yet, pain remains one of the most under treated symptoms. The American Geriatrics Society suggests that 45 to 80 percent of long-term residents have substantial untreated pain.¹ In another study, a random selection of hospitalized medical and surgical patients revealed that 80 percent reported pain with 45 percent describing it as “excruciating.”²

The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has set standards for appropriate assessment and treatment of pain. The surge in interest in the pain management field is accompanied by a rise in the use of opioids throughout the United States. It is therefore necessary that pain clinicians become familiar with opioids and their characteristics.

Morphine remains the gold standard for the treatment of moderate to severe pain. This ancient opioid has been very well studied and thus will be used as the prototype for this class of medications in the remaining text. In addition, the majority of equianalgesic charts use morphine as the basis on which they build their dosing.

Opioid rotation (OR) involves switching one opioid to another, and when applicable, a route to another, to optimize analgesia and lessen side effects. The rotation can be performed between different long-acting opioids, or from short- acting to long-acting opioids to establish stable analgesia, and minimize the risks of tolerance and addiction.³ The routes that are commonly switched are from Intravenous (IV) to subcutaneous (SQ), oral (PO) to SQ, or IV to PO.⁴ A listing of studies related to opioids rotation is shown in Table 1.

TABLE 1: Listing of studies related to opioid rotation

Indications for Opioid Rotation

The decision to rotate opioids remains almost purely clinical. However, there are at least three situations where OR may be indicated:

1. Severe/excessive side effects;
2. Neurotoxicity, including delirium, myoclonus, hyperalgesia, and allodynia;
3. Convenience and cost benefits.

Hyperalgesia/Allodynia

Hyperalgesia is defined as an excessive response to a painful stimulus. Allodynia is pain due to a touch or temperature stimulus that normally does not provoke pain. Hyperalgesia has been described as a clinical paradox of pain.⁵ It has an important clinical relevance; often, it is mistaken for worsening pain and is treated with more narcotics with worsening clinical outcome. Hyperalgesia and allodynia can result from high doses of morphine both in humans^5-6 and in animals.⁷ Both can result from high levels of Morphine-3-Glucuronide (M3G) one of the established morphine metabolites.⁸ Accumulation of M3G is a result of high systemic doses of morphine. Accumulation of metabolites such as norhydromorphone, normeperidine, and others may result in these manifestations but because morphine is the prototype of opioids it remains well studied.

Severe/Excessive Side Effects

To better understand the indications for OR, it is recommended that pain clinicians become familiar with the traditional and emerging side effects of opioids. (See Table 2.)

TABLE 2: Traditional and emerging side effects of opioids

Approximately 80 percent of cancer patients require opioid analgesics for the treatment of their pain at some point before death.⁹ In the majority of cases, these patients will develop serious side effects requiring a change of the type of opioid at least once.¹

Neurotoxicity

Neurotoxicity can result in delirium, hallucinations, myoclonus, and cognitive failure. Recent findings demonstrate that opioid rotation should be attempted in patients who develop neuropsychiatric toxicity.⁸ This toxicity is the result of accumulation of active metabolites of the commonly used opioids such as morphine and hydromorphone (Dilaudid).⁸

Delirium

Delirium is an acute confusing state that is found to be significantly higher than was originally thought; about 80 percent of patients with advanced cancer develop delirium during the last week of life.¹¹ It can be divided into three subtypes: hypoactive (withdrawn), hyperactive (agitated), and mixed. Clinically, it is an important entity in patients that are chronically on large doses of opioids regardless of the etiology of their disease; addressing this issue is of prime importance as it changes the way these patients are treated. For example, hypoactive delirium may be wrongly diagnosed as depression and inappropriately treated with antidepressants. Similarly, agitated delirium may be wrongly assessed as anxiety and treated with benzodiazepines, which will further complicate the clinical picture.¹² All may be needed is opioid rotation.

Hallucinations

It is not uncommon for patients on chronic opiates to experience hallucinations. Usually, these are visual¹³ but tactile hallucinations are more frequent.¹⁴ They are usually part of a broader complex of signs and symptoms called Opioid-Induced Neurotoxicity (OIN).¹⁵ This syndrome is most often seen in patients with prolonged use of high dose opioids, borderline cognition, dehydration, renal insufficiency, concomitant use of psychoactive drugs, and advanced age.¹⁵ Ruling out other causes of hallucinations is essential.

Myoclonus

Myoclonus is the spontaneous twitching or jerking of muscles. It can be unifocal (one limb) or multifocal (multiple extremities). Generalized myoclonus can also occur. In our experience, this last entity, more frequent with meperidine, can frequently be mistaken for seizures and thus unnecessarily treated with anticonvulsants. Myoclonus related to opioids can be divided into three categories:¹⁶

• Opiate-induced myoclonus (OIM) — Often generalized, periodic, or associated with rigidity.
• Intrathecal OIM — Usually associated with the administration of opioids in the subarachnoid space.
• Opiate withdrawal myoclonus — This may be stimulus-sensitive and associated with D2 antagonists.

In 1998, Sjogren et al indicated that elevated concentrations of M3G in the plasma and elevated ratio of M3G/M6G in both the plasma and CSF might play a role in the development of myoclonus.¹⁷

Convenience and Cost Benefits

Switching routes of administration can result in more convenience for the patient and possibly improving compliance as well. The routes that are commonly switched are from IV to SQ, PO to SQ, or IV to PO.⁴ For example, an inpatient with advanced or terminal disease necessitating venous delivery of opioids may have SQ delivery of these medications. This will be more convenient, cost effective, and will not hamper or delay discharge planning from the hospital.

Switching routes of administration can result in more convenience for the patient and possibly improving compliance as well.

Opioid rotation may often result in substantial cost savings via a number of avenues, some tangible and others less tangible. Tangible cost savings include reduced cost of the “new” drug being rotated to, decreased needs for resources required to manage side effects and neurotoxicity, cost savings via route of administration (i.e. switching from IV to SQ), and decreased service utilization when the pain and its side effects are under control.

In order to illustrate the potential cost savings, methadone, for example, as a target drug for rotation will be used. Success of rotation by switching to methadone has been favorably reported in recent literature.^18-21 This drug costs 15 to 20 times less than other opioids at equivalent dosage.^19,22 Since methadone has no known active metabolites, the likelihood of neurotoxicity due to accumulation of active metabolites is significantly reduced.^15,23 Because of its dual effects on opioid receptors and NMDA receptors, methadone may produce tolerance less frequently than other opioids. Because of its presumed NMDA receptor antagonist effect, it is possible to use this agent without an “anti-neuropathic” agent such as Gabapentin, which is relatively expensive.

Recent data suggest that constipation may develop at a much slower pace in patients receiving methadone vis-à-vis other opioids.²⁴ Reduction in constipation and laxative requirements following opioid rotation to methadone has been reported.²⁰ As a long acting drug, methadone can be administered two to three times daily, and once a day dosing has also been reported.²⁵ Less frequent dosing has been associated with increased compliance and thus, reduced cost.

There are less tangible but equally substantial cost savings that can be accrued from opioid rotation. While the immediate focus of pain management has often been on pain reduction/control, loss in productivity and quality of life resulting from ineffective pain management can be equally, if not more, costly. The staggering cost of disability resulting from poorly managed pain has been well documented.²⁶ Sedation, mental clouding, and apathy in addition to other physical side effects such as constipation, nausea, and orthostatic hypotension can significantly compromise patient functioning, productivity, and quality of life.

Physicians have often underestimated the psychological and emotional impact of ineffective opioid management resulting in poorly managed pain as well as ineffective side effects management. For instance, patients sometime decide unilaterally to stop taking their opioids or not to take them as directed even though it has helped reduce their pain. The cost of a compromised quality of life such as these cannot be assigned dollar equivalence but has increasingly become a factor, which must be addressed in the design of a modern health care service delivery. An effective opioid rotation program may help to reduce, if not, eliminate the compromised quality of life concern secondary to ineffective opioid management and the management of its side effects.