Recent research suggests that the morphine derivative morphine-6-O-sulfate may provide a more potent treatment for acute, chronic and cancer-related pain in patients, whilst having a reduced number of unwanted side effects.
A novel drug, morphine-6-O-sulfate, has been reported by Joseph Holtman Jr and colleagues as potentially being more potent and longer lasting than morphine in the treatment of pain in rats. The research was carried out at the University of Kentucky‘s College of Medicine (KY, USA), Holtman has since moved to Loyola University (IL, USA).
Morphine, oxycodone and hydrocodone are µ-opioids that bind to specific opioid receptors in the central and peripheral nervous systems, and are considered the primary drugs for treating acute, chronic and cancer-related pain in patients. The potential pain relieving drug morphine-6-O-sulfate, is a derivative of morphine.
Holtman and colleagues treated rats with both morphine and morphine-6-O-sulfate – orally, intravenously and via injection into the space surrounding the spinal cord. Various tests were carried out to assess the rats‘ sensitivity to pain, including shining a warm light beam onto their tail to test nociceptive pain. The time it took for them to flick their tails away was recorded. It was discovered that morphine-6-O-sulfate was ten-times more potent than typical morphine when administered into the space surrounding the spinal cord, five-times more potent intravenously and twice as potent when taken orally. Furthermore, morphine-6-O-sulfate maintained its greatest effects for twice as long as morphine, lasting for 3 h.
Holtman and colleagues also found morphine-6-O-sulfate to be more potent in neuropathic and inflammatory pain, where morphine is not typically as effective. The neuropathic test was carried out using chronic constriction nerve injury and allodynia, and the inflammatory pain was created via a formalin test.
There are many side effects associated with morphine, including constipation, nausea, vomiting and drowsiness. Constipation can result in extended hospital stays as consultants are not able to discharge surgery patients until they have had a bowel movement. It can also prevent patients from taking prescribed morphine for pain management as it can make them extremely uncomfortable. Promising results by Holtman suggest that, whilst morphine-6-O-sulfate can cause constipation, this is only at doses 10–20-times higher than the effective dose for pain management.
Another major problem with morphine is the ability of the patient to build up tolerance to the drug, this occurred within 10 days in the rats. However, it took 25 days for tolerance to build up to morphine-6-O-sulfate. These results show great potential and have led Holtman and colleagues to describe the novel drug as “an interesting drug for further study”.
The funding company InSys Therapeutic, Inc. has a license to potentially develop the drug for use in humans.
Source: Holtman HR Jr, Crooks PA, Johnson-Hardy J, Wala EP: Antinociceptive effects and toxicity of morphine-6-O-sulfate sodium salt in rat models of pain. Eur. J. Pharmacol. 648(1–3), 87–94 (2010).
Patients with anesthetized arms reported experiencing false senses, which provides hope that alterations in the brain‘s plasticity during anesthesia may hold future hope for amputee patients suffering from phantom limb pain.
Stein Silva and colleagues from the Inserm research team (Toulouse, France) have been studying the illusions described by patients who have been given local anesthetic in their arms and investigating how this affects brain activity and interferes with body perception.
Silva and colleagues wanted to identify how neuronal circuits are rearranged during anesthesia and whether this could be used in the treatment of patients suffering from ‘pain‘ in amputated limbs, known as phantom limb pain. It is believed that phantom limb pain is caused by the plasticity of the brain following trauma, which causes inaccurate depictions of the missing body part. Patients who have been given localized anesthetic describe the same false perceptions.
The Inserm research team wanted to assess whether anesthesia could provoke a comparable phenomena in the brain. They took 20 patients who had one of their arms anesthetized for surgery and showed them 3D images of the hand from a variety of angles. The team then evaluated how well the patients managed to differentiate between the right and the left hand. Major trends were seen between the patients during local arm anesthesia; they all reported false senses in their arms, and their speed and efficiency to differentiate between the right and left hand deteriorated.
Ultimately, the changes in the way we perceive our own body during lower arm anesthesia are caused by modified brain activity. Silva and colleagues are now investigating functional brain imaging to locate the areas of the brain that are affected. They hope that anesthesia could be used therapeutically in patients who have had limbs amputated and still experience pain by altering postlesional plasticity.
Source: Silva S, Loubinoux I, Olivier M et al.: Impaired visual hand recognition in preoperative patients during brachial plexus anesthesia. Anesthesiology 114(1), 126–134 (2011).
How much pain a patient is experiencing is largely subjective to that person, and makes the assessment by researchers and physicians particularly difficult. Current measurements of pain consist of a 0–10 scale, where 0 corresponds to no pain at all and 10 suggests unbearable pain. However, one person‘s 4 may be another person‘s 7. Therefore, in a clinical trial, for example, when the efficiency of a new drug is being tested, subjective views of pain make the overall effectiveness of pain management by the drug difficult to assess. In addition, for some people just being treated may decrease their sensitivity to pain without actually physically changing the level of pain experienced.
Sean Murphy and colleagues from Washington State University (WA, USA) have compared this traditional method of pain perception with a new more ‘fuzzy‘ pain model that prevents certain subjective bias and have examined how often pain is misclassified by patients. Murphy and colleagues discovered that the chance of perceived pain being incorrectly classified by a patient was between 3–14%. This incorrect classification is caused by patients both mistakenly thinking they have not improved when they have and, equally, that they have improved when in fact they have not. They concluded that researchers, physicians and policy makers must be careful when assessing therapy efficiency if exclusively relying on subjective pain reports.
Murphy and colleagues now wish to extend this research to further confirm these results.
Source: Murphy SM, Rosenman R, Friesner DL, Raisor J: A cautionary note on the use of perceived pain scores in health outcomes research. Int. J. Behav. Healthcare Res. 2, 123–135 (2010).
Stimulation of the vagus nerve via transcutaneous vagus nerve stimulation may increase the human pain threshold without producing the side effects seen in some drug-based therapies.
A new study into the pain-relieving effects of transcutaneous vagus nerve stimulation (t-VNS) has been investigated by Peter Eichhammer and Volker Busch from the University of Regensburg (Regensburg, Germany), who collaborated with medical device company, Cerbomed (Erlangen, Germany).
Stimulation of the vagus nerve has been previously demonstrated to adjust nociception and pain processing in animals and human experimental studies. However, direct stimulation of this nerve is extremely invasive, which has led to the development of the t-VNS.
Eichhammer, Volker and colleagues took 48 healthy human subjects (24 male and 24 female) and tested somatosensory processing using a quantitative sensory testing protocol with mechanical and thermal stimulation. Each subject was tested with and without the t-VNS device.
The results suggested that there was a significant difference between mechanical pain perception with and without the t-VNS, and that, when the t-VNS was applied, the pressure–pain threshold increased.
“Until now, the analgesic effect of vagus nerve stimulation has only been proven in animal experiments, and only occasionally observed in people with invasive vagus nerve stimulation,” says Busch. “Now, however, for the first time, this effect could be proven with t-VNS in a randomized, controlled study in humans.”
Jens Ellrich, Chief medical officer at Cerbomed, emphasizes the importance of these alternative options for pain management caused by the unwanted side effects of some drug-based therapies, “The results and findings from this preclinical study make planning further clinical studies into the therapy of chronic pain with t-VNS possible.”
Source: Cerbomed press release: www.cerbomed.com/index.php?lang=en#pressrelease_a_new_study_proves_the_painkilling_effect
A new drug delivery system, ViaDor™, may be as effective as previous methods in administering Calcitonin in the treatment of osteoarthritis and musculoskeletal pain.
A self-applied ViaDor™-Calcitonin (previously known as ViaDerm-Calcitonin) product has had promising results in Phase I clinical trials carried out by TransPharma Medical Ltd (Lod, Israel).
Calcitonin is currently available in subcutaneous, intramuscular and nasal route forms for the treatment of postmenopausal osteoporosis, hypercalcemia and Paget‘s disease. However, the ViaDor drug delivery system is a hand-held electronic device that creates microscopic channels through the skin‘s outer layer, permitting transdermal delivery via a patch on the skin of many different drugs, including Calcitonin.
The TransPharma Medical trial of ViaDor-Calcitonin included 12 postmenopausal women who were subjected to four different concentrations of Calcitonin (60–300 µg). The safety, pharmacokinetics and pharmacodynamics of the system were then assessed. There was a clear pharmacokinetic dose response, which corresponded to the increasing doses of the ViaDor-Calcitonin patches. In addition, a statistically significant decrease in bone resorption and cartilage degradation biomarkers (CTX-I and -II) was seen when a single dose of ViaDor-Calcitonin was applied, a similar level to that of the current subcutaneous injection of Calcitonin, Miacalcin®, suggesting that this form of drug delivery may be just as effective.
It is hoped that the new form of drug delivery system will be advantageous to previous options because it is cost effective, easy to use, virtually pain free and self-administered. Daphna Heffetz, the CEO of TransPharma Medical stated that the company “is very pleased with the results of this study, which demonstrate that our transdermal Calcitonin is safe and as efficacious as a subcutaneous injection,” and that “it leads us to believe that enhancing these capabilities with the ease of use, virtual painlessness, small size and portability of our ViaDerm system may open up a myriad of possibilities to expand the therapeutic applications of Calcitonin beyond the current approved indications.”
Source: TransPharma Medical press release: www.transpharma-medical.com/press171020.html