In Reply:—

We appreciate the comments of Drs. Kirkpatrick and Herndon regarding the safety and effectiveness of intraspinal morphine for the relief of chronic pain. We noted that they specifically objected to our reference to morphine as the “gold standard” for intrathecal analgesic therapy. They also highlight the fact that long-term intraspinal administration of this compound involves managing certain well-known complications and necessitates attention to the potential for unknown risks. In reply, we assert that, because morphine is the only drug approved for intraspinal delivery by the Food and Drug Administration for pain and is used widely in this context to treat acute pain successfully worldwide, it is, by default, the standard against which all other intrathecal analgesics are compared. For example, opiates were used as the reference analgesics in 37 of 50 clinical studies we found that were published in 1999 and 2000, and morphine was the reference drug in 19 of these studies. Yet, as we noted in the introduction to our review and as Drs. Kirkpatrick and Herndon reiterate in their letter, the medical complications, scientific uncertainties, and socioeconomic questions regarding long-term use of intrathecal morphine motivate the desire to identify new drugs or drug combinations that may qualify as improved “platinum standards” for the treatment of pain. The main goal of our review was to inform readers of potential candidates for this future role. Finally, Drs. Kirkpatrick and Herndon note that studies that directly compare the effectiveness of systemic versus  intraspinal analgesics for long-term control of chronic pain, both cancer- and non–cancer-related, are needed. At least one such study, a randomized, controlled trial comparing maximal medical therapy versus  intrathecal therapy in patients with cancer pain, is now in progress at 26 centers worldwide. 1The study compares pain relief, quality of life, and cost effectiveness of the two drug administration approaches (systemic and intrathecal). Seventy-four cancer patients, whose pain is not controlled adequately with 200 mg systemic morphine equivalent or who have uncontrolled side effects, have been randomized to receive maximal medical therapy or intrathecal therapy. It is hoped that this project will be completed by the end of 2001 and will help to define better the role of intraspinal analgesics for chronic pain.

As an addendum to our previous work, readers should note that new potential targets for intrathecal analgesia regimens have been introduced in the literature during or after publication of our review. Potential neurotransmitter targets now also include the cannabinoid and vanilloid receptor systems. Intrathecal administration of WIN55, 2122, an agonist for the cannabinoid 1 receptor, had no effect on baseline paw withdrawal latency to punctate mechanical stimuli in rats but reduced mechanical hyperalgesia after paw inflammation. 2Resiniferatoxin, an ultrapotent agonist for the vanilloid (capsaicin) 1 receptor, produced thermal analgesia 4–6 h after epidural administration in rats, which lasted more than 7 days. 3The list of potential neuromodulator targets also has been extended. Intrathecal administration of [Phe1(CH2NH)Gly2]nociceptin(113)NH2, a pseudopeptide analog of nociceptin, produced a dose-dependent increase of tail flick latency in rats that lasted up to 1 h. 4 

We appreciate the comments of Drs. Kirkpatrick and Herndon. Although it is clearly the clinical standard, we agree that morphine may not qualify as “gold.” The main point of our review, however, was not to evaluate morphine rigorously but to inform readers that there are many agents that, alone or in combination, may become new, improved “platinum standards” for the intraspinal treatment of pain.

Staats PS: A multicenter, randomized controlled trial of intrathecal vs. systemic therapy for chronic cancer pain. American Pain Society Abstracts 1999; 18: 181
Martin WJ, Loo CM, Basbaum AI: Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Pain 1999; 82: 199–205
Szabo T, Olah Z, Iadarola MJ, Blumberg PM: Epidural resiniferatoxin induced prolonged regional analgesia to pain. Brain Res 1999; 840: 92–8
Wang Y-Q, Zhu C-B, Cao X-D, Wu G-C: Supraspinal hyperalgesia and spinal analgesia by [Phe1Ψ(CH2-NH)Gly2]nociceptin-(1-13)-NH2in rat. Eur J Pharmacol 1999; 376: R1–3