Rational Analgesic Polypharmacotherapy: A Novel Treatment Approach in Pain Management

Joseph Solberg, DO

Hunter Vincent, DO

FAST FACTS

1. Rational analgesic polypharmacotherapy (RAPP) is a novel multidimensional approach to combination drug therapy, which places greater emphasis on a patient’s comorbid medical conditions, medication side effect profile, and drug mechanism of action to provide safer and more efficacious pain management.
2. If a combination of 2 medications does not deviate significantly from the individual dose response curve, then the drugs are considered additive. However, if the addition of a second drug creates a larger pain-relieving effect, they are considered supra-additive or synergistic.

Any treatment algorithm for managing pain is often met with significant barriers owing to the subjective nature of pain, variable intensity, and biopsychosocial factors that influence the patient experience. Although a multimodal approach to pain management is often efficacious, it is important to understand the role of pharmacotherapy. Identifying the cause of a painful condition, whether it be mechanical, neuropathic, inflammatory, cancer-related, or a combination of these is integral in determining which pharmacologic intervention is most applicable. Research has investigated a pharmacologic strategy known as combination drug therapy (CDT), which in theory involves the use of additive or synergistic drugs to achieve more effective pain relief.¹ However, because of our incomplete understanding of pain mechanisms, a paucity of clinical research, and vast medication options, most applications of CDT are largely based on clinical experience and anecdotal evidence. A safer and more appropriate approach to pharmacologic intervention with CDT is termed rational analgesic polypharmacotherapy (RAPP). This incorporates a multidimensional perspective of a patient’s unique clinical history and pain symptoms (see Figure 5-1).

RAPP is a novel multidimensional approach to CDT, which places greater emphasis on a patient’s comorbid medical conditions and medication side-effect profile. This approach utilizes scientific principles to create a more individualized multidrug pain management regimen tailored to each individual patient. When utilizing RAPP, it is important to understand the therapeutic interactions between medications. By definition, if a combination of 2 medications does not deviate significantly from the individual dose response curve, then the drugs are considered additive. However, if the addition of a second drug creates a larger pain-relieving effect, they are considered supra-additive or synergistic.¹ The pain-relieving effects of this multidrug approach can be achieved via drugs of the same class with differing pharmacokinetics, drugs of different drug classes, or different combinations of drugs with different routes of administration. RAPP also uses strategies such as medication cycling, which limits consistent exposure to 1 specific medication or combines drugs at lower doses to reduce overall side effects of individual medications. In this chapter, we will discuss the principles of RAPP
in the context of different pain generators, which will form a preliminary framework for a safe and novel pharmacologic algorithm.

FIGURE 5-1 Summary of the sites of action of the major drug classes used for pain management. Analgesics target various steps in pain perception, from the initiation of a pain stimulus to the central perception of that pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) modulate the initial membrane depolarization (signal transduction) in response to a peripheral stimulus. Sodium channel blockers decrease action potential conduction in nociceptive fibers. Opioids, antidepressants, NSAIDs, antiepileptic drugs (anticonvulsants), and α2-adrenergic agonists all modulate transmission of pain sensation in the spinal cord by decreasing the signal relayed from peripheral to central pain pathways. Opioids also modulate the central perception of painful stimuli. The multiple sites of action of analgesics allow a combination drug approach to be used in pain management. For example, moderate pain is often treated with combinations of opioids and NSAIDs. Because these drugs have different mechanisms and sites of action, the combination of the drugs is more effective than one drug alone. Reprinted with permission from Golan DE. Principles of Pharmacology. 4th ed. Philadelphia, PA: Wolters Kluwer; 2016.

PAIN GENERATORS

Determining the pain generators will help in the choice of most appropriate analgesic classes. For example, a combination including opioid medications may be appropriate for a patient with pain due to malignancy but not for chronic nonmalignant low back pain. Therefore, we will discuss RAPP approaches in different clinical scenarios, with the understanding that there very well may be multiple concurrent pain generators (i.e., nociceptive, neuropathic, cancer pain).

Neuropathic Pain

Neuropathic pain can be caused by a variety of conditions both centrally and peripherally mediated, allowing for multiple target treatment areas.² Pharmacotherapy is a fundamental part of multimodal therapy in the treatment of neuropathic pain, with drug classes encompassing antiepileptic, antidepressant, gabapentanoid, and opioid analgesics, which all have multiple routes of administration. However, many of these medications have dose-related side effects as well as other contraindications. In addition, the overall efficacy of many neuropathic medications for chronic nonmalignant pain has been called into question.³^,⁴ Initiating a pharmacologic regimen for neuropathic pain with a single agent as opposed to multiple medications simultaneously allows for observation of medication side effects and tolerability. The European Federation of Neurological Societies published guidelines in 2010 on neuropathic pain pharmacotherapy, which recommended using single drugs at relatively high doses (up to 150 mg for tricyclic antidepressants, 3600 mg of gabapentin, 400 mg of tramadol) as the first and second lines of treatment, whereas combination therapies are recommended for patients who show only partial response to drugs administered alone.⁵ It is not uncommon for patients suffering from neuropathic pain to need multiple medications to provide analgesia. If there is inadequate response to a single agent, the principles of RAPP apply.

When determining which medications to initiate for combination therapy under the RAPP approach, a stepwise decision process should be used (see Figure 5-2). It is important to first evaluate the patient’s medical history/comorbidities, current medication regimen, as well as allergies. For example, a tricyclic antidepressant is not the ideal choice in a patient with cardiac arrhythmia because of potential cardiotoxic, proarrhythmic side effects. In addition, it could potentially cause worsening mental status and sedation. Likewise, duloxetine would not be a good first choice in a patient already on a selective serotonin and/or norepinephrine reuptake inhibitor such as sertraline or venlafaxine owing to the medication’s serotonergic effects and the potential to cause serotonin syndrome. It is also important to identify
risk factors such as renal disease, liver disease, and previous adverse reactions, which can all place a patient at higher risk for side effects or negative outcomes.¹

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