A new study undertaken by researchers in synthetic organic chemistry, published in an advanced online edition of the journal Nature Chemistry, has resulted in the successful creation of a rare analgesic – normally only found in the bark of the plant Tabernaemontana divaricata. With an ever increasing need to source pain medication, the study provides a strong basis for the creation of new analgesics in a laboratory setting.
The purpose of this investigation was to develop a technique to create modern synthetic molecules useful in the treatment of pain, in particular, the creation of conolidine, the molecule found in the bark of a plant often used in traditional medicine. Speaking to Pain Management, Glenn Micalizio, senior author of the paper and an Associate Professor in the Department of Chemistry at The Scripps Research Institute (FL, USA), relayed to us the importance of this work: “The most significant aspect of the current advance is that we have described the first laboratory synthesis of a rare natural molecule that exists in minute quantities in a tropical flowering plant historically used in traditional medicine. In fact, our synthesis of conolidine enabled the first assessment of its pharmacological profile as an analgesic – a study that concluded that conolidine is a potent nonopioid analgesic.”
Whilst conolidine has been used for some time in traditional medicine for the treatment of pain, the molecule is incredibly rare and thus difficult to study. Through the synthesis of conolidine (a member of the C5-nor stemmadenines alkaloid group), Micalizio has provided both the means to create the potential analgesic in useful quantities and the ability to test the effectiveness of the molecule in clinical situations.
Although there is a need for newer nonopioid analgesics (owing to the numerous side effects associated with commonly used opioids such as morphine) Micalizio explained to Pain Management about being cautious about the future: “Projections regarding clinical utility can only be speculative, at best. Our laboratory is a chemical synthesis laboratory, and my collaborator, Professor Laura Bohn, is a pharmacologist in the Department of Molecular Therapeutics at Scripps. We are clearly a very long way from delivering a drug to market. Without detailed understanding of the pharmacological mechanism of action, the potential clinical utility of conolidine (and related analogs) remains quite speculative.”
However, Micalzio still remains optimistic, as preliminary results are promising: “With that said, conolidine possesses potent analgesic properties – in some assays, it appears nearly as potent as morphine. Professor Bohn has validated that conolidine is not acting as an opiate, and as such should not have a similar side-effect profile as classic opioid analgesics (addiction, nausea, depression of breathing and chronic constipation). The chemical synthesis pathway defined provides the fundamental scientific foundation to begin the pursuit of C5-nor stemmadenines as potential nonopioid analgesics.”
It is clear that this experiment is an important step in the creation of pharmaceuticals useful in the treatment of pain. It is hoped that through further understanding and research, more molecules could be synthesized to suit the wide profiles of pain management.
Source: Tarselli MA, Raehal KM, Brasher AK et al. Synthesis of conolidine, a potent non-opioid analgesic for tonic and persistent pain. Nat. Chem. 6, 449–453 (2011).
A recent study has demonstrated promising early results for the use of microgel particles in the treatment of back pain. Chronic back pain can be caused by degeneration of the intervertebral discs and the research team from the University of Manchester (UK) hope that the work they have conducted can form the basis of a method of permanently replacing the workings of the intervertebral disc. Tony Freemont from the University of Manchester School of Biomedicine described some of the problems caused by this type of back pain, “Degeneration of the intervertebral disc results in chronic back pain which costs the country billions of pounds per annum and causes untold misery for sufferers and their families … We have been working for 25 years to identify methods for treating degeneration of the intervertebral disc.”
It has been demonstrated previously that an injectable fluid of singly crosslinked, pH-responsive microgel particles can form a gel that is capable of restoring the mechanical properties of models of damaged discs. The University of Manchester team have now advanced this research; they have covalently linked the microgel particles to form pH-responsive doubly crosslinked microgels.
The new microgels were found to have improved mechanical properties compared with the earlier microgels and could undergo significant changes in form for long periods without breaking; these are improvements that were necessary in order for the microgel technology to have the durability that is essential in a medical device.
Commenting on the results of the study, Brian Saunders, the lead researcher of the team, from the University of Manchester School of Materials, said, “Our team has made a breakthrough through innovative materials design that brings the prospect of an injectable gel for treating degeneration of the intervertebral disc a step closer.”
Sources: The University of Manchester: www.manchester.ac.uk/aboutus/news; Liu R, Milani AH, Freemont TJ, Saunders BR. Doubly crosslinked pH-responsive microgels prepared by particle inter-penetration: swelling and mechanical properties. Soft Matter 7, 4696–4704 (2011).
A new analysis of a 2-year study, published in The Journal of Bone and Joint Surgery, has looked at the effectiveness of interventions for the treatment of contiguous spinal disk damage. The study looked at the improvement in patients who had undergone either the commonly used spine fusion technique or the process of artificial disc replacement in over 200 patients, demonstrating that whilst both interventions were relatively effective, the patients tended to prefer the artificial disk replacement.
The study compared both interventions to ascertain which was more favorable in terms of the safety of the procedure and the benefit that the patient received. Similar studies have looked at these outcomes, but have not been applied to situations wherein there are two worn out contiguous discs. Rick Delamarter, first author of the study and Vice Chair for Spine Services in the Department of Surgery and Co-Medical Director of the Spine Center at Cedars-Sinai Medical Center (Los Angeles, CA, USA) commented on the study: “Overall, 24 months after surgery, patients in both groups had less pain and were able to reduce their use of medication, but the percentages were higher in the disc replacement group. 73% of disc replacement patients met the study‘s pain improvement criteria, compared with less than 60% of the fusion patients. Of these, only 19% in the disc replacement group continued to need narcotics for pain, compared with 40% in the fusion group. Also, more disc replacement patients said they were satisfied with their outcomes and would choose to have the surgery again.”
Normally vertebral discs serve to cushion the vertebrae in the spine. However, when these become worn or damaged, they are unable to act as a support structure, which can result in nerves being pressed on between the vertebrae, leading to spinal pain. The two interventions in this study rectify this problem, but with different approaches. Fusion surgery utilizes rods and poles to encourage growth of bone, effectively fusing the vertebrae together. This can lead to greater stress on the other vertebrae and a reduction in movement and flexibility. The artificial disc approach replaces the worn out disc with an artificial equivalent, which may provide better flexibility and a reduction in the need for further surgery.
Commenting on the future prospects of the study, Delamarter said: “Although our data extend 2 years out from surgery, fully evaluating the benefits or disadvantages of either procedure will require longer follow-up to detect adjacent-level disc degeneration and possible device wear.”
Whilst chronic lower back pain remains a significant burden to many individuals, continuing studies and trials are beginning to highlight and reveal the most effective interventions for dealing with this affliction.
Source: Delamarter R, Zigler JE, Balderston RA, Cammisa FP, Goldstein JA, Spivak JM. Prospective, randomized, multicenter Food and Drug Administration investigational device exemption study of the ProDisc-L total disc replacement compared with circumferential arthrodesis for the treatment of two-level lumbar degenerative disc disease: results at twenty-four months. J. Bone Joint Surg. Am. 93(8), 705–715 (2011).
A paper published in Journal of Neuroscience has examined in great detail the link between chronic lower back pain and cognitive impairment. Specifically, the effects of treating lower back pain on the morphological and functional activity of the brain. The project utilized MRI scanners to detect these changes in patients over a 6-month time period in the McGill University Health Centre (Montreal, Canada).
Whilst the association of chronic pain and physical and functional brain alterations has been observed before, this investigation looked at whether this effect could be reversed through the treatment of pain. The researchers selected patients who had been experiencing chronic lower back pain for more than 6 months. These patients were scanned prior to and 6 months after treatment (consisting of either surgery or spinal injections). The results not only demonstrated an increase and recovery in morphological changes within the brain, including the cortical thickness which was shown to be reduced in these pain sufferers, but also an improvement in cognitive functioning as measured using functional MRI.
In a statement to Pain Management, David Seminowicz, first author of the paper and researcher at the University of Maryland (Baltimore, MD, USA), formerly of McGill University, commented on the challenges of the project: “One of the major challenges was that for many people with low back pain, being in the MRI scanner can be a painful experience. We developed a scanning protocol that could be completed in 20 minutes. Most participants reported having no pain during this short session. This was particularly important for the functional MRI sessions, where we could show that the differences were related to long-term alterations to brain functional networks, and not simply an effect of being in pain during the scan.”
The study has revealed some interesting aspects of the association between brain activity and how patients‘ brains alter over time in response to medical interventions. “We now know that treatment directly influences brain structure and function, and that the more effective the treatment is, the better some of those brain outcomes are. The implication is that treating pain can do much more than provide pain relief: it has effects on brain areas involved in attention, decision-making and emotion regulation,” said Seminowicz to Pain Management.
When asked about the future prospects, Seminowicz replied: “As a future aim, we hope that results like ours will identify brain targets for treatment. For example, if we target the left dorsolateral prefrontal cortex, can we decrease pain and/or pain-related disability? A few studies using brain stimulation techniques have provided some evidence that this could work. One area of investigation that needs to be expanded is whether pre-treatment brain imaging can predict treatment-related outcomes. If that were the case it would help clinicians further personalize pain treatments.”
Source: Seminowicz DA, Wideman TH, Naso L et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J. Neurosci. 31(20), 7540–7550 (2011).