Morphine Microdose Therapy Safe, Effective in Chronic Non-Cancer Pain

Morphine microdose therapy may be successful in a community pain clinic setting in achieving analgesia, improving safety, and avoiding systemic side effects, according to results from a retrospective review published in Pain Medicine.¹

Denise M. Wilkes, MD, PhD, from the department of anesthesiology and pain medicine at the University of Texas Medical Branch in Galveston, Texas and colleagues retrospectively reviewed the charts of 60 patients with chronic, non-cancer pain who had completed a microdose morphine regimen and had an intrathecal (IT) pump implanted between June 2008 and October 2014. During IT therapy, the researchers recorded dose changes over time, pain scores, side effects, and maximum dose.

“The morphine microdose method involves a pretrial reduction or elimination of systemic opioids followed by a period of abstinence,” the researchers wrote. After the period of abstinence, IT morphine is initiated at doses <0.2 mg per day. After pump implant and morphine monotherapy, systemic opioid abstinence is continued.

Researchers found that out of the 60 patients analyzed, 35 (58%) successfully reported adequate pain management by morphine microdose therapy alone, without the need for additional oral pain medications.

Mean pain scores were significantly reduced from 7.4±0.32 at baseline to 4.8±0.3 after microdose therapy.

“The safety of IT therapy was increased by using a lower concentration (2 mg/mL) and lower daily doses (<3 mg/day) of morphine,” the researchers noted. “Microdose therapy was feasible, safe, and cost-effective in the outpatient setting.”

Safety

The biggest benefit of the microdose method is safety. Its low dose decreases the occurrence of catastrophes due to programming errors or bridge bolus errors, and reduces the effect of adverse effects, especially the formation of catheter tip granuloma.

“Although catheter tip granuloma is rare, if not recognized and treated appropriately, irreversible neurological damage can ensue. Therefore, the most important advantage of the microdose method is safety,” the researchers wrote.

Upper Limit of Microdose Therapy

A previous trial examined factors that contribute to granuloma formation and found that both dose and concentration of morphine were major factors.² In that study by Rui Duarte, PhD from Birmingham City University in the United Kingdom, and colleagues, the median dose of morphine was 2.8 mg/day, and 15 mg/day in the granuloma-free and granuloma groups, respectively. They also found that the mean concentration of morphine in the granuloma group was 20 mg/mL.

In the current study, doses of morphine remained well below the granuloma group, and the concentration of morphine was 2 mg/mL.

“Theoretically, even our patients in the higher dose escalation group would require approximately 29 years to reach the dose of the [granuloma] group,” wrote Dr Wilkes and colleagues. “The mean time span for granuloma formation reported by Duarte, et al was 39.5±13.5 months.³ Our patients had a duration of therapy of up to 1634 days (54.5 months = 4.5 years) without incidence of granuloma formation.”

There is still much debate about the definition of the microdose method and its upper limit. “We suggest that the upper limit is the dose at risk for catheter tip granuloma formation,” the researchers wrote.

Cost

While initially intrathecal drug delivery systems (IDDS) cost more than systemic opioid management, the cost is offset by the second year.⁴

“The outpatient microdose trialing method significantly reduces the first-year costs of IDDS. For example, in our area, the cost for a Medicare patient with one to two comorbidities for outpatient trial is $855 compared with $5600 for an inpatient trial,” the researchers wrote.

Discontinuing systemic opioid management after IDDS implantation has also been shown to reduce cost by 10% to 12% in annual inpatient, outpatient, and drug expenditures.⁵

Summary & Clinical Applicability

The results of this trial showed that microdose therapy was feasible, safe, and cost-effective in an outpatient setting.

“The 10-fold lower concentration practically eliminates the risk of granuloma formation. The microdose method [also] improves safety by decreasing the life-threatening consequences of programming errors and dosing errors,” the researchers wrote.

However, it is unknown how factors such as dose, concentration, infusion rate, and/or opioid abstinence contribute to the success of microdose therapy. Further research is needed to determine the impact these factors have on microdose therapy’s success.

Limitations & Disclosures

• Study limitations are related to its retrospective nature. Selecting patients who are able to wean and are willing to commit to a microdose strategy can affect outcomes
• Researchers chose to focus on the morphine microdose method and did not evaluate other regimens such as hydromorphone or ziconotide
• This trial studied only patients who had a successful trial and implant; patients who did not were put in another trial with either an increased dose of morphine or a morphine alternative such as hydromorphone or ziconotide

Denise Wilkes, MD, PhD: research funded by Medtronic; journal club funded by Medtronic.

Susan J. Orillosa, MD, Eric C. Hustak, MD, Courtney G. Williams, MD, Gulshan R. Doulatram, MD, Daneshvari R. Solanki, FRCA, Eduardo A. Garcia, MD: journal club funded by Medtronic.

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References

1. Wilkes DM, Orillosa SJ, Hustak EC, et al. Efficacy, safety, and feasilbility of the morphine microdose method in community-based clinics [published online June 13, 2017]. Pain Med. doi:10.1003/pm/pnx132
2. Duarte RV, Raphael JH, Southall JL, Baker C, Ashford RL. Intrathecal granuloma formation as result of opioid delivery: Systematic literature review of case reports and analysis against a control group. Clin Neurol Neurosurg. 2012;114(6):577-584.
3. Duarte RV, Raphael JH, Haque MS, Southall JL, Ashford RL. A predictive model for intrathecal opioid dose escalation for chronic non-cancer pain. Pain Physician. 2012;15(5):363-369.
4. Guillemette S, Witzke S, Leier J, Hinnenthal J, Prager JP. Medical cost impact of intrathecal drug delivery for noncancer pain. Pain Med. 2013;14(4):504-515.
5. Hatheway JA, Caraway D, David G, et al. Systemic opioid elimination after implantation of an intrathecal drug delivery system significantly reduced health-care expenditures. Neuromodulation. 2015;18(3):207-213;discussion 13.