Intrathecal Drug Delivery and Spinal Cord Stimulation for Cancer Pain: A Review

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Randomized trials with large samples are needed to further explore the use of intrathecal drug delivery systems and spinal cord stimulation to inform cancer treatment guidelines.
Randomized trials with large samples are needed to further explore the use of intrathecal drug delivery systems and spinal cord stimulation to inform cancer treatment guidelines.

Cancer-related pain affects approximately 9 million people worldwide each year, with the number of new cases expected to increase from 12.7 million in 2008 to 22.2 million by 2030.1,2 Cancer pain has been linked to reduced quality of life, increased risk for depression, and reduced tolerance to cancer treatment.3

The management of cancer pain is gradually shifting from a stepwise approach to a multimodal approach that includes the early implementation of interventional pain procedures. A review published in Current Pain and Headache Reports examines the evidence and current practices pertaining to 2 such procedures: intrathecal drug delivery systems (IDDS) and spinal cord stimulation (SCS).3

Intrathecal drug delivery systems

Intrathecal vs systemic drug delivery offers the advantages of requiring lower drug doses, being associated with fewer adverse effects, being more (cost-)effective, and being less toxic. In addition, IDDS does not interfere with chemotherapy or radiotherapy.

Intrathecal therapy is typically indicated for patients who have not adequately responded to conventional pharmacologic treatment, or those for whom these treatments are associated with adverse effects. The review authors noted that although results of numerous studies indicate benefits of IDDS for cancer pain, the quality of the evidence is generally low because of small sample sizes or flaws in methodology.

Although morphine and ziconotide are the only analgesic agents approved by the US Food and Drug Administration for intrathecal therapy, "the off-label use of hydromorphone and sufentanil in combination with adjuncts such as bupivacaine, baclofen, and clonidine inside the intrathecal space are largely accepted by expert consensus" for cancer pain management, they reported.

Morphine. In a randomized clinical trial published in 2002, intrathecal delivery of morphine and comprehensive medical management were examined in 202 patients with refractory cancer pain receiving a 200 mg/day oral morphine regimen.4 Patients receiving intrathecal morphine vs comprehensive medical management reported improvements in visual analog scale (VAS) pain scores (reduction of 3.90 vs 3.05, respectively) and medication-related fatigue and sedation, and had improved toxicity scores (50% vs 17% reduction, respectively) and 6-month survival (53.9% vs 37.2%, respectively).

In prospective studies, intrathecally delivered combinations of medications, such as morphine/ropivacaine and baclofen/clonidine, were found to improve refractory cancer pain. In a double-blind crossover study, morphine-sparing effects were observed when dexmedetomidine was combined with morphine, with no serious adverse effects reported.5

"Overall, there are insufficient human studies supporting the use of intrathecal octreotide, neostigmine, adenosine, baclofen, clonidine, midazolam, and ketamine for cancer pain although experts recommend their use (with the exception of dexmedetomidine and adenosine) should first-line medications fail to produce sufficient analgesia," the review authors stated.

Ziconotide. A randomized placebo-controlled trial examined the effects of intrathecal ziconotide in 95 patients with cancer and 13 patients with AIDS, all with refractory pain (ie, VAS pain intensity score [VASPI] >50 mm despite prior treatment with systemic and/or intrathecal analgesics).6 Patients receiving ziconotide vs placebo had greater improvements in VASPI scores (53.1% vs 18.1%, respectively; P <.001), and a higher percentage of patients reporting serious adverse events (30.6% vs 10.0%, respectively).

In a randomized trial of patients with noncancer pain, the slow titration of ziconotide during a 3-week period vs placebo was associated with greater improvements in VASPI scores (14.7% vs 7.2%, respectively) and comparable prevalence of adverse effects, suggesting this approach may mitigate the elevated rates of adverse effects previously observed with ziconotide.7

Ongoing studies investigate the intrathecal delivery of novel analgesic agents, including AYX1, an inhibitor of transcription factor EGR1; resiniferatoxin, a capsaicin analog that targets the TRPV1 receptor; and other conopeptides in addition to ziconotide, including MrVIB, pyroglutamate-1-MrIA, and Con-G.

Spinal cord stimulation

Although the efficacy of SCS is supported primarily by small case reports and case series,8 the "Polyanalgesic Consensus Conference algorithm recommends its use for neuropathic cancer pain if symptom coverage can be achieved with a stable disease course," according to the present review.

In an observational study of 15 patients with low back pain associated with colorectal cancer or angiosarcoma, SCS resulted in a >50% improvement in VAS scores at 12 months. Opioid discontinuation and reduction was observed in 8 and 5 patients, respectively.9 Similar outcomes were found in a case series of 14 patients with lung cancer and chest wall pain related to thoracotomy or postoperative radiation.10 Multiple case reports also support the effectiveness of SCS for pain after surgery, chemotherapy, and radiation in patients with several types of cancer.

Although large randomized trials are needed to further determine the benefits of and inform treatment guidelines pertaining to IDDS and SCS, these "therapies are increasingly utilized as tools in a multimodal strategy for pain control and should not necessarily be reserved for patients in extremis or those who have 'failed' more conservative therapies," the authors of the current review concluded. Given the lack of high-quality evidence to date, the "rationale and choice of treatment must be individualized and relies upon careful weighing of risks and benefits that include shared decision-making with patients."      

Clinical Pain Advisor asked Krishnan V. Chakravarthy, MD, PhD, assistant clinical professor of anesthesiology and pain medicine at the University of California, San Diego, to weigh in on these findings, their clinical implications, and the remaining research needs.

Clinical Pain Advisor: What do the findings suggest thus far about the potential role of IDDS and SCS for cancer pain?

Dr Chakravarthy: It is clear that both IDDS and SCS may serve as excellent options for palliative care, and specifically for patients [with cancer]. Although spinal cord stimulation may have broad applicability outside of cancer pain, the 1 area that has good clinical indication for IDDS is in palliative care. This is mainly because of a shortage of viable intrathecal opioid-sparing alternatives. This is an area of future exploration and ongoing research.

Clinical Pain Advisor: What are the main clinical implications of these findings?

Dr Chakravarthy: I think these studies warrant greater reflection on the role of these therapies within the cancer pain treatment paradigm. Likely, as more randomized controlled data gathering is encouraged, there will be greater emphasis on these therapies as viable options.

Clinical Pain Advisor: What should future research in this area focus on?

Dr Chakravarthy: With regard to IDDS therapy, [research on] opioid-sparing intrathecal alternatives should be emphasized. Large randomized controlled trial data support [the notion] that long-term opioid therapy with no defined clinical end point leads to more adverse effects than benefits. We must [therefore] be cognizant of those findings when using this approach to manage cancer pain. However, the strongest support for IDDS therapy is in cancer pain, where patient life expectancy plays an important role in determining duration of therapy, and patient comfort is a vital consideration. SCS could represent an exciting alternative approach to cancer pain treatment and needs to be further explored.

References

  1. Lee SK, Dawson J, Lee JA, et al. Management of cancer pain: 1. Wider implications of orthodox analgesics. Int J Gen Med. 2014;7:49-58.
  2. Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human Development Index (2008-2030): a population-based study. Lancet Oncol. 2012;13(8):790-801.
  3. Xing FYong RJKaye ADUrman RD. Intrathecal drug delivery and spinal cord stimulation for the treatment of cancer pain. Curr Pain Headache Rep. 2018;22(2):11.
  4. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002;20(19):4040-4049.
  5. Liu HJ, Gao XZ, Liu XM, Xia M, Li WY, Jin Y. Effect of intrathecal dexmedetomidine on spinal morphine analgesia in patients with refractory cancer pain. J Palliat Med. 2014;17(7):837-840.
  6. Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or aids: a randomized controlled trial. JAMA. 2004;291(1):63-70.
  7. 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 Manag. 2006;31(5):393-406.
  8. Peng L, Min S, Zejun Z, Wei K, Bennett MI. Spinal cord stimulation for cancer-related pain in adults. Cochrane Database Syst Rev. 2015;6:CD009389.
  9. Yakovlev AE, Resch BE. Spinal cord stimulation for cancer-related low back pain. Am J Hosp Palliat Care. 2012;29(2):93-97.
  10. Yakovlev AE, Resch BE, Karasev SA. Treatment of cancer-related chest wall pain using spinal cord stimulation. Am J Hosp Palliat Care. 2010;27(8):552-556.


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