Novel combination for pain treatment
Tramadol plus paracetamol effective v. acute, chronic pain
Pain, the most common complaint for which patients seek medical attention, often remains undertreated. This undertreatment, according to Dr. Ravi K. Desiraju, results from "patients and physicians [fearing] the adverse events associated with the commonly available pain drugs." Speaking at a luncheon symposium organized by Janssen Pharmaceutica during the Philippine College of Physicians annual convention last year, Desiraju said "no analgesic is perfect." Neither can one drug treat all kinds of pain, but clinical outcomes can be improved by combining one analgesic with another, said Desiraju, a research scientist in the field of drug metabolism and lead researcher in the development of new drugs for the central nervous system and pain management.
"A combination is most effective when the individual agents act through different analgesic mechanisms but act synergistically," he explained. "By activating these multiple pain pathways, combination analgesics can provide more effective pain relief for a broader spectrum of pain patients and might also reduce the adverse drug reactions, because you will be using less drug of each of these individual drugs in the combination."
Tramadol and paracetamol are two analgesics that can be combined. (The combination is marketed in the Philippines as Dolcet.)
Tramadol and paracetamol are neither nonsteroidal antiinflammatory drugs (NSAIDs) nor COX-2 inhibitors; they are not pure opioid agonists, either. Tramadol has opioid and nonopioid mechanisms. It is a "weak opioid agonist," said Desiraju, and a weak inhibitor of norepinephrine and serotonin reuptake. Its risk of abuse is low, according to the United States Food and Drug Administration and the World Health Organization.
The rationale for combining the two drugs is based on their pharmacokinetics. Tramadol is a slow-acting, long-duration analgesic. It reaches peak effect in two to three hours; it has a plasma half-life of six hours. Paracetamol, on the other hand, is a rapid-acting, short-duration analgesic. It reaches peak effect in 30 minutes but plasma half-life is only two hours. Combining the two drugs makes for a compound that has fast onset of action and long duration of action lasting.
Efficacy, tolerability in acute pain
The efficacy of Dolcet has been tested in patients with postsurgical dental pain, which is a "model for acute pain." In a study involving 456 postoperative-dental-pain patients (Fricke et al., 2004), Dolcet proved to be more efficacious than tramadol and placebo (both p < 0.001) in the following areas-pain relief, pain intensity, time to onset of pain analgesia, and overall medication rating. Dolcet provided both rapid onset of action and longer-lasting pain relief after a single dose with fewer side effects, particularly nausea (33 percent v. 46 percent in tramadol; p = 0.019).
Dolcet has also shown efficacy in osteoarthiritc flares. In a randomized, placebo-controlled, add-on study (Silverfield et al., 2002) involving 308 patients, the mean pain-relief scores showed a statistically significant difference between placebo and Dolcet (p < 0.001). This significant difference in pain relief was seen across all age groups, including the elderly.
Desiraju concluded: "Dolcet as add-on therapy leverages multiple mechanisms of action, and it provided better pain relief than antiinflammatory therapy alone. Dolcet was effective and well tolerated."
Dolcet in chronic pain
Dolcet has also been tested in chronic pain and its various manifestations-chronic back pain, osteoarthritis, fibromyalgia, and diabetic neuropathy, among others.
In the osteoarthritis study (Rosenthal et al., 2002), Dolcet was compared with placebo as an add-on treatment to COX-2 inhibitors (celecoxib or rofecoxib). Patients were maintained on a titration schedule until day 10 and subsequently allowed to titrate their dose (one to two tablets) four times daily.
In terms of pain relief (using the pain visual-analog scale), Dolcet offered statistically significant improvement compared with placebo after 91 days (p < 0.025). Furthermore, although patients were allowed to take up to a maximum of eight tablets per day of Dolcet, the average dose they took was only between four and five tablets daily. "There's a very good window of safety," Desiraju said.
In a placebo-controlled, double-blind trial, patients with diabetic peripheral neuropathy given Dolcet reported greater decreases in pain intensity and sleep interference than those on placebo (both p < 0.001). Significantly more patients on Dolcet reported at least a 30-percent improvement in terms of pain relief (p = 0.001) than patients on placebo.
Desiraju also noted that pain relief was seen in the Dolcet group after the first week of treatment, and sustained for 66 days. "It was not just somewhere in the middle, but it was right in the beginning," he stressed.
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