Guidance for Treatment Selection for Severe, Refractory Chronic Pain

In an effort to synthesize best practices for intrathecal (IT) therapy, researchers conducted a literature review of 2 agents approved by the US Food and Drug Administration (FDA) for analgesia by intrathecal injection—morphine and ziconotide—and published their findings in Pain Practice.¹ This review, based on medical literature and recommendations from a panel of experts who convened at the Polyanalgesic Consensus Conference,² summarizes criteria for successful use of IT therapy for the management of refractory pain, including selection of patients and IT agents.

A leading cause of disability worldwide, chronic pain affects more than 100 million adults in the United States and constitutes a heavy economic burden, with an annual cost of $560 to $635 billion.³

Severe, chronic pain is initially often managed by systemic drug delivery (usually opioids and nonsteroidal anti-inflammatory drugs), off-label prescription of antidepressants or anticonvulsants, and physical therapy.⁴ Pain is considered refractory when these conventional therapeutic options are ineffective. In such cases, interventional pain management treatments such as spinal cord stimulation (SCS) and IT therapy are both indicated and effective.^{5, 6} However, adequate guidelines regarding selection of appropriate pain care modalities among the many available options are not available.

IT therapy provides advantages over systemic or oral delivery in that it is directly injected to the vicinity of spinal receptors and ion channels. It also avoids the potential for overdose associated with these more conventional therapies.

Researchers at the Center for Pain Relief in Charleston, West Virginia, proposed a new definition of refractory pain, separate from its etiology, in an effort to change attitudes toward the use of interventional pain management options as an early treatment modality.⁷ They consider pain to be refractory “when (1) multiple evidence-based biomedical therapies used in a clinically appropriate and acceptable fashion have failed to reach treatment goals that may include adequate pain reduction and/or improvement in daily functioning or have resulted in intolerable adverse effects, and when (2) psychiatric disorders and psychosocial factors that could influence pain outcomes have been assessed and appropriately addressed.”

Patient Selection for IT Therapy

IT therapy can be considered when SCS fails, but also as an alternative to SCS.¹ Several factors must be considered prior to IT drug delivery, which has proven effective in treating nociceptive, neuropathic, and mixed pain, both in the presence and absence of cancer.^{8, 9} Individuals for whom pain is localized are considered ideal candidates for IT pain management, as this therapy allows for drug delivery at anatomically appropriate spinal cord sites.

Patients who are responsive to systemic opioids can be considered for IT delivery of morphine. Those experiencing neuropatic pain, visceral pain, complex regional pain syndrome, as well as those for whom opioid use causes concern, can be considered for IT ziconotide delivery. Ziconotide, a N-type calcium channel blocker, has proven effective in relieving both neuropathic and nociceptive pain, rendering this agent a first-line treatment of choice, along with opioids.¹

In order to ensure compliance to IT treatment, which involves an implantable device and regular clinician visits, a psychological assessment is recommended to identify personality and/or cognitive disorders that might impede therapy success. In addition, ziconotide is contraindicated in patients with a history of psychosis.¹⁰ In those patients, IT morphine might still be considered.

Concerns Associated With IT Therapy

Patients undergoing IT treatment might experience headaches and facial pain. Those with ischemic heart disease, heart failure, or cerebrovascular disease are not appropriate candidates for IT therapy. Adequate caregiver support and/or sufficient independence are also essential factors for effective IT therapy, as patients need to manage the complexity of frequent appointments.

Starting IT Therapy

Treatment initiation requires practical considerations related to device implantation in order to minimize risk of infection and to avoid device malfunction and programming errors. In addition, catheter tip should be positioned in close proximity to the primary pain generator. The Polyanalgesic Consensus Conference recommended IT morphine dosage of 0.1 to 1.0 mg/d for patients without morphine tolerance.² Delivery of IT ziconotide requires initial titration in an effort to limit adverse effects, with a recommended starting dosage of 2.4 µg/d, with slow titration to determine optimal dosage.²

Considerations for Long-term IT Therapy

IT therapy is associated with a number of adverse effects that need to be managed in the long-term. These include catheter-tip granuloma, hypogonadism, peripheral edema, and opioid tolerance in the case of IT morphine. IT ziconotide delivery has been associated with CNS-related adverse effects (memory impairment, confusion, dizziness, psychosis), as well as urinary retention, elevation of creatine kinase levels, and nausea.¹¹ The IT ziconotide-related CNS effects may be worsened by concomitant use of anticonvulsants or antidepressants.¹¹

Patients should be monitored for these various therapy-related adverse effects, and dose adjustment might be necessary to provide an appropriate balance between therapy efficacy and tolerability.

IT therapy represents a valuable option for a large proportion of patients with severe, refractory chronic pain. Treatment should be appropriately selected, adjusted, and adequately managed in the long-term to ensure optimal pain relief.

References

1. Pope JE, Deer TR, Bruel BM, Falowski S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. Pain Pract. 2016 Feb 23. doi: 10.1111/papr.12438. [Epub ahead of print]

2. Carrillo-Ruiz JD, Andrade P, Godinez-Cubillos N, et al. “Polyanalgesic Consensus Conference 2012: Recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel” by Timothy R. Deer, MD et al., that was published in your prestigious journal under the following reference: Neuromodulation 2012;15:436-466. Neuromodulation. 2013;16(4):387.

3. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163-2196.

4. Chou R. 2009 Clinical Guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in chronic noncancer pain: what are the key messages for clinical practice?. Pol Arch Med Wewn. 2009;119(7-8):469-77.

5. Hayes C, Jordan MS, Hodson FJ, Ritchard L. Ceasing intrathecal therapy in chronic non-cancer pain: an invitation to shift from biomedical focus to active management. PLoS ONE. 2012;7(11):e49124.

6.. Mejía-Terrazas GE, López-Ruiz VG, Infante-Cosío G, Carapia-Sadurni A, Hernández-Méndez-Villamil E. [Spinal cord stimulation in teenager with complex regional pain syndrome for Lyme’s disease. Case report and review of the literature]. Acta Ortop Mex. 2015;29(4):228-231.7. Deer TR, Caraway DL, Wallace MS. A definition of refractory pain to help determine suitability for device implantation. Neuromodulation. 2014;17(8):711-715.

8.. Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006;31(5):393-406.

9. Wallace MS, Charapata SG, Fisher R, et al. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation. 2006;9(2):75-86.

10. Pope JE, Deer TR. Ziconotide: a clinical update and pharmacologic review. Expert Opin Pharmacother. 2013;14(7):957-66.

11. Ruan X. Drug-related side effects of long-term intrathecal morphine therapy. Pain Physician. 2007;10(2):357-366.