Intrathecal Therapy for Chronic Pain: A Review of Morphine and Ziconotide as Firstline Options

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Abstract

Objectives

To evaluate the evidence for morphine and ziconotide as firstline intrathecal (IT) analgesia agents for patients with chronic pain.

Methods

Medline was searched (through July 2017) for “ziconotide” or “morphine” AND “intrathecal” AND “chronic pain,” with results limited to studies in human populations.

Results

The literature supports the use of morphine (based primarily on noncontrolled, prospective, and retrospective studies) and ziconotide (based on randomized controlled trials and prospective observational studies) as first-choice IT therapies. The 2016 Polyanalgesic Consensus Conference (PACC) guidelines recommended both morphine and ziconotide as firstline IT monotherapy for localized and diffuse chronic pain of cancer-related and non–cancer-related etiologies; however, one consensus point emphasized ziconotide use, unless contraindicated, as firstline IT therapy in patients with chronic non–cancer-related pain. Initial IT therapy choice should take into consideration individual patient characteristics (e.g., pain location, response to previous therapies, comorbid medical conditions, psychiatric history). Trialing is recommended to assess medication efficacy and tolerability. For both morphine and ziconotide, the PACC guidelines recommend conservative initial dosing strategies. Due to its narrow therapeutic window, ziconotide requires careful dose titration. Ziconotide is contraindicated in patients with a history of psychosis. IT morphine administration may be associated with serious side effects (e.g., respiratory depression, catheter tip granuloma), require dose increases, and cause dependence over time.

Conclusion

Based on the available evidence, morphine and ziconotide are recommended as firstline IT monotherapy for cancer-related and non–cancer-related pain. The choice of first-in-pump therapy should take into consideration patient characteristics and the advantages and disadvantages of each medication.

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Most cited references 70

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Vital signs: overdoses of prescription opioid pain relievers---United States, 1999--2008.

(2011)

Overdose deaths involving opioid pain relievers (OPR), also known as opioid analgesics, have increased and now exceed deaths involving heroin and cocaine combined. This report describes the use and abuse of OPR by state. CDC analyzed rates of fatal OPR overdoses, nonmedical use, sales, and treatment admissions. In 2008, drug overdoses in the United States caused 36,450 deaths. OPR were involved in 14,800 deaths (73.8%) of the 20,044 prescription drug overdose deaths. Death rates varied fivefold by state. States with lower death rates had lower rates of nonmedical use of OPR and OPR sales. During 1999--2008, overdose death rates, sales, and substance abuse treatment admissions related to OPR all increased substantially. The epidemic of overdoses of OPR has continued to worsen. Wide variation among states in the nonmedical use of OPR and overdose rates cannot be explained by underlying demographic differences in state populations but is related to wide variations in OPR prescribing. Health-care providers should only use OPRs in carefully screened and monitored patients when non-OPR treatments are insufficient to manage pain. Insurers and prescription drug monitoring programs can identify and take action to reduce both inappropriate and illegal prescribing. Third-party payers can limit reimbursement in ways that reduce inappropriate prescribing, discourage efforts to obtain OPR from multiple health-care providers, and improve clinical care. Changes in state laws that focus on the prescribing practices of health-care providers might reduce prescription drug abuse and overdoses while still allowing safe and effective pain treatment.

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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.

Eric Buchser, Peter Staats, … (2002)

Implantable intrathecal drug delivery systems (IDDSs) have been used to manage refractory cancer pain, but there are no randomized clinical trial (RCT) data comparing them with comprehensive medical management (CMM). We enrolled 202 patients on an RCT of CMM versus IDDS plus CMM. Entry criteria included unrelieved pain (visual analog scale [VAS] pain scores >/= 5 on a 0 to 10 scale). Clinical success was defined as >/= 20% reduction in VAS scores, or equal scores with >/= 20% reduction in toxicity. The main outcome measure was pain control combined with change of toxicity, as measured by the National Cancer Institute Common Toxicity Criteria, 4 weeks after randomization. Sixty of 71 IDDS patients (84.5%) achieved clinical success compared with 51 of 72 CMM patients (70.8%, P =.05). IDDS patients more often achieved >/= 20% reduction in both pain VAS and toxicity (57.7% [41 of 71] v 37.5% [27 of 72], P =.02). The mean CMM VAS score fell from 7.81 to 4.76 (39% reduction); for the IDDS group, the scores fell from 7.57 to 3.67 (52% reduction, P =.055). The mean CMM toxicity scores fell from 6.36 to 5.27 (17% reduction); for the IDDS group, the toxicity scores fell from 7.22 to 3.59 (50% reduction, P =.004). The IDDS group had significant reductions in fatigue and depressed level of consciousness (P <.05). IDDS patients had improved survival, with 53.9% alive at 6 months compared with 37.2% of the CMM group (P =.06). IDDSs improved clinical success in pain control, reduced pain, significantly relieved common drug toxicities, and improved survival in patients with refractory cancer pain.

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Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial.

R Luther, Susan Wallace, David Ellis … (2004)

Ziconotide (formerly SNX-111) selectively blocks N-type voltage-sensitive calcium channels and may be effective in patients with pain that is refractory to opioid therapy or those with intolerable opioid-related adverse effects. To assess the safety and efficacy of intrathecal ziconotide in patients with pain that is refractory to conventional treatment. Double-blind, placebo-controlled, randomized trial conducted from March 12, 1996, to July 11, 1998, at 32 study centers in the United States, Australia, and the Netherlands. Patients were 111 individuals ages 24 to 85 years with cancer or AIDS and a mean Visual Analog Scale of Pain Intensity (VASPI) score of 50 mm or greater. Patients were randomly assigned in a 2:1 ratio to receive ziconotide or placebo treatment. Intrathecal ziconotide was titrated over 5 to 6 days, followed by a 5-day maintenance phase for responders and crossover of nonresponders to the opposite treatment group. Mean percentage change in VASPI score from baseline to the end of the initial titration period. Of the evaluable population, 67 (98.5%) of 68 patients receiving ziconotide and 38 (95%) of 40 patients receiving placebo were taking opioids at baseline (median morphine equivalent dosage of 300 mg/d for the ziconotide group and 600 mg/d for the placebo group; P =.63, based on mean values), and 36 had used intrathecal morphine. Mean (SD) VASPI scores were 73.6 (1.8) mm in the ziconotide group and 77.9 (2.3) mm in the placebo group (P =.18). Mean VASPI scores improved 53.1% (95% confidence interval [CI], 44.0%-62.2%) in the ziconotide group and 18.1% (95% CI, 4.8%-31.4%) in the placebo group (P<.001), with no loss of efficacy of ziconotide in the maintenance phase. Pain relief was moderate to complete in 52.9% of patients in the ziconotide group compared with 17.5% in the placebo group (P<.001). Five patients receiving ziconotide achieved complete pain relief, and 50.0% of patients receiving ziconotide responded to therapy compared with 17.5% of those receiving placebo (P =.001). Intrathecal ziconotide provided clinically and statistically significant analgesia in patients with pain from cancer or AIDS.

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Author and article information

Journal

Journal ID (nlm-ta): Pain Med

Journal ID (iso-abbrev): Pain Med

Journal ID (publisher-id): painmedicine

Title: Pain Medicine: The Official Journal of the American Academy of Pain Medicine

Publisher: Oxford University Press

ISSN (Print): 1526-2375

ISSN (Electronic): 1526-4637

Publication date (Print): April 2019

Publication date (Electronic): 22 August 2018

Publication date PMC-release: 22 August 2018

Volume: 20

Issue: 4

Pages: 784-798

Affiliations

[1 ]The Center for Pain Relief, Spine and Nerve Centers of The Virginias, Charleston, West Virginia

[2 ]Thrive Clinic, Santa Rosa, California

[3 ]Jacksonville Spine Center, Jacksonville, Florida

[4 ]Integrated Pain Solutions, Columbus, Ohio, USA

Author notes

Correspondence to: Timothy R. Deer, MD, The Center for Pain Relief, The Spine and Nerve Center of the Virginias, 400 Court Street, Ste 100, Charleston, WV, USA 25301. Tel: 304-347-6120; Fax: 304-347-6126; E-mail: doctdeer@ 123456aol.com .

Article

Publisher ID: pny132

DOI: 10.1093/pm/pny132

PMC ID: 6442748

PubMed ID: 30137539

SO-VID: c231d36c-c98c-46f8-a69a-97d5120edce0

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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Pages: 15

Funding

Funded by: Jazz Pharmaceuticals 10.13039/100011096

Funded by: Synchrony Medical Communications, LLC

Funded by: MedErgy

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Intrathecal Therapy for Chronic Pain: A Review of Morphine and Ziconotide as Firstline Options

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Most cited references 70

Vital signs: overdoses of prescription opioid pain relievers---United States, 1999--2008.

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.

Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial.

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