When traditional oral analgesics no longer control pain, some physicians are turning to alternative drug delivery methods that provide pain relief while avoiding systemic adverse effects (AEs).1 Intrathecal (IT) drug delivery may offer patients more sustained relief for localized, neuropathic pain because it targets the kappa-opioid receptors without the mu-opioid receptor effects, which can produce respiratory depression, euphoria, and dependence.1

For years, the US Food and Drug Administration had approved only 2 drugs for IT administration for pain relief: ziconotide and preservative-free morphine.1 Many of the drugs expert consensus recommends are used off-label in IT therapy:1,2

  • Hydromorphone
  • Fentanyl
  • Sufentanil
  • Bupivacaine
  • Clonidine

Patient Selection Is Critical

Although physicians acknowledge that IT therapy is not for every patient with chronic pain, select therapies may have enduring relief.1 To that end, the Polyanalgesic Consensus Conference (PACC) convened in 2016 to recommend best practices for IT therapy.2 Some of the patient and therapy considerations include:

  • Type and location of pain
  • Age
  • Prior opioid exposure
  • Patient comorbidities
  • Catheter location
  • IT space pharmacokinetics
  • Physiochemical properties of medication
  • Device variables
  • Cerebral spinal fluid flow dynamics

The patients who experience the greatest success with IT therapy tend to have localized pain, although some IT experts say that patients with diffuse pain can be treated this way.1 For elderly patients, IT therapy may provide alternative analgesia to reduce polypharmacy and the adverse effects of oral and transdermal medications.3

“[IT] opioid therapy is indicated only in a small portion of all patients with chronic pain,” explained Tilman Wolter, MD, PhD, from the Interdisciplinary Pain Center, University Hospital Freiburg in Germany. “In Germany, estimates range in the order of 12 million patients with chronic pain, and there are about 2000 pump implantations per year, just to illustrate the order of magnitude. Nonetheless, in carefully chosen patients, younger and elderly patients, [IT] opioid therapy can be an option.”

Switching From Systemic to IT Therapy

One of the most challenging aspects of pain management is maintaining analgesia from oral systemic medications to adequate levels delivered intrathecally. In a 4-year retrospective study of 220 patients with cancer (mean age, 62±12 years; 43% women) with refractory pain, only 32% achieved early pain relief, defined as 0 to 7 days after implantation of an IT device. One factor that contributed to early pain relief was using an appropriate initial ratio of local anesthetic to morphine, although the researchers caution there is no one correct formula.4

Not surprisingly, patients whose performance status was better fared better in converting from oral medications to IT delivery.

“Patients try more than 2 or 3 different medications before IT treatment. We fight to implant patients sooner with lower doses and after only an opioid trial, especially for some cancers where IT is very effective, like pancreatic cancer or Pancoast-Tobias syndrome,” told Denis Dupoiron, MD, anesthesiologist from the Western Cancer Institute in Angers, France, in an interview with Clinical Pain Advisor.

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Caveats Abound

Although the PACC provides detailed guidance based on literature and consensus, it does acknowledge that the variables of pump, surgical placement, infection, and medication can contribute to overall outcomes.2 Moreover, respiratory depression can still occur in the case of a morphine overdose.3

When pumps malfunction, physicians typically assess the problem with magnetic resonance imaging; however, for patients who are allergic to iodine that is used with imaging, another contrast medium must be used.5 Although not without risk, gadolinium-based contrast agents may provide an alternative to such patients. To that end, anesthesiologist and pain specialist Jonathan M. Hagedorn, MD, from the Mayo Clinic, Rochester, Minnesota, and colleagues compiled case reports to better inform physicians of problems that the PACC guidelines do not address.

“My goal with writing this paper was to provide physicians with a thorough review of [IT] gadolinium use and guidelines for safe [IT] gadolinium use,” explained Dr Hagedorn. “There have been disastrous consequences secondary to [IT] gadolinium use; my hope is that it won’t happen again.”

Long-Term IT Therapy

To better assess the efficacy of long-term IT therapy, neurosurgeon Björn Sommer, MD, from the University of Medicine Göttingen in Germany, and colleagues retrospectively studied 27 patients with chronic, nonmalignant pain (mean age, 64.0±8.9 years; 52% women) beyond 10 years.6

Researchers assessed patients with the Numerical Rating Scale for pain before and after 1, 3, 5, and 10 years after IT pump implantation. The preoperative Numerical Rating Scale score was 9.0±0.9, and 1 year after pump implantation, the mean score was 6.7±1.8. Most (88.9%) of the patients who received IT therapy said they would agree to implantation again.6 The most common AEs were perspiration, infection at the catheter site requiring corrective surgery, nausea and vomiting because of morphine dosage, and catheter dislocation. IT therapy was not responsible for any permanent morbidity or deaths during the study.6

“Long-term pain reduction and patient satisfaction was still present after 15 to 20 years after implantation of the first IT pump in our patient cohort,” Dr Sommer told Clinical Pain Advisor. “Therefore, clinicians can review additional long-term data provided by our article to advise patients.”

Summary and Clinical Applicability

For patients with neuropathic pain refractory to conventional oral medications, IT drug delivery may provide longer-lasting relief. Off-label uses of drugs abound in this area because only ziconotide and preservative-free morphine are approved by the US Food and Drug Administration for IT delivery.

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References

1. Deer TR, Malinowski M, Varshney V, Pope J. Choice of intrathecal drug in the treatment of neuropathic pain – new research and opinion. Expert Rev Clin Pharmacol. 2019;12(10):1003-1007.

2. Deer TR, Pope JE, Hayek SM, et al. The Polyanalgesic Consensus Conference (PACC): recommendations for intrathecal drug delivery: guidance for improving safety and mitigating risks. Neuromodulation. 2017;20(2):155-176.

3. Kleinmann B, Wolter T. Managing chronic non-malignant pain in the elderly: intrathecal therapy. Drugs Aging. 2019;36(9):789-797.

4. Dupoiron D, Leblanc D, Demelliez-Merceron S, et al. Optimizing initial intrathecal drug ratio for refractory cancer-related pain for early pain relief. A retrospective monocentric study. Pain Med. 2019;20(10):2033-2042.

5. Hagedorn JM, Bendel MA, Moeschler SM, Lamer TJ, Pope JE, Deer TR. Intrathecal gadolinium use for the chronic pain physician. Neuromodulation. 2019;22(7):769-774.

6. Sommer B, Karageorgos N, AlSharif M, Stubbe H, Hans FJ. Long-term outcome and adverse events of intrathecal opioid therapy for non-malignant pain syndrome [published online July 10, 2019]. Pain Pract. doi:10.1111/papr.12818