Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management

Kalle Varav, M.D.

GR Lauretti, ICPR Lima, M Reis, WA Prado, NL Pereira, Anesthesiology, 90: June 1999

The development of tolerance and the high incidence of side effects with escalating doses of opioids in the management of chronic and cancer pain, is an all too common phenomenon.

This pilot study attempts to determine clinically whether the effect of oral opioids can be potentiated, and whether the development of tolerance can be suppressed with the use of co-analgesics. Theoretically at least, activation of the NMDA receptor and production of Nitric Oxide are known to be involved in the development of opioid tolerance. Nitric Oxide has also been shown to interact synergistically with morphine in producing analgesia. Additionally, Ketamine Hydrochloride (KG), an NMDA antagonist, has been shown to have activity at opiate, cholinergic, adrenergic, and 5-HT systems, as well as local anesthetic properties of action potential blockade.

In this prospective, non-blinded study, 60 patients with cancer-related pain were randomly divided into 4 groups of 15. All patients were initially taking between 80-90mg of oral morphine and 50mg of oral amitryptiline daily. Pain was assessed using a Visual Analog Scale (VAS) (0-10). There were no differences among groups regarding age, gender, weight, height, primary cancer site or VAS scores before initiation of oral morphine treatment. Patients were treated with the study protocol when their pain levels were rated as 4/10 or worse. The first group of 15 served as the control group (CG), and subjects received an additional 20mg of oral morphine (10mg at 12hr intervals). The second group (DG) received 500mg of dipyrone (a NSAID) at 6-hour intervals. The third group (KG) received ketamine 0.5mg/kg orally at 12hr intervals, and the 4th group (NG) received a 5mg transdermal Nitroglycerin patch daily. After the test protocol, patients were allowed to manipulate their daily morphine consumption by requesting additional oral morphine to their 80-90 mg pre-study dose in order to maintain a VAS less than 4/10. Daily morphine requirement and VAS scores were recorded on days 1,5,10,15, 20, and 30.

Results of this pilot study revealed a significantly lower consumption of morphine in the ketamine and Nitroglycerin treated groups compared to the control and Dipyrone group on Days 15, 20, and 30. Additionally, patients in the control and Dipyrone group reported more somnolence, constipation, nausea and other side effects compared to the other study groups. There was, however, one incidence of intense headache in the NG group, and one incidence of hallucination in the KG group.

The authors conclude that ketamine and nitroglycerin may be effective coadjuvants to opioid therapy and include a theoretical discussion to explain their findings. Although this is intended to be a pilot study and lacks in its sample size, the outcome is promising because both objective and subjective measures are evaluated. Ketamine is itself a potent analgesic with multiple mechanisms for its effects as mentioned above, and one would anticipate an additive effect when co-administered with opioids. However, nitroglycerin has no analgesic properties alone, and these findings encourage the continued search for adjuvant medications. A decrease in pain, side effects, and opioid requirement may encourage clinicians to consider the use of these adjuvants in their own clinical practice. In addition, further investigation is warranted to evaluate the joint administration of these adjuvants with opioids as well as a comparative efficacy with other NMDA antagonists, such as dextromethorphan and amantadine, as well as other nitric oxide donors.