A new perspective paper published in the International Journal of Clinical Practice has suggested that antidepressants can be useful for the treatment of painful conditions such as osteoarthritis, and may lead to fewer side effects than commonly prescribed drug regimes, such as anti-inflammatories and opioids.
The authors of the paper, Leslie Citrome (Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College, NY, USA) and Amy Weiss-Citrome (Pomona, NY, USA) examined studies looking at the effects of duloxetine being used on its own or in combination with NSAIDs. The two randomized double-blind, placebo-controlled clinical trials that formed the basis of US FDA approval of duloxetine for the treatment of chronic pain associated with osteoarthritis were included within these studies.
The number needed to treat (NNT) and number needed to harm (NNH) were quantified in order to highlight how many patients needed to be treated with one intervention versus another before encountering one additional patient who experiences a desired outcome (NNT) or undesired disadvantage, such as a side-effect (NNH). A smaller number signifies a greater advantage for NNT and a greater disadvantage for NNH.
“Applying these simple methods to often complex research gives us a real indication of whether a drug will benefit or harm our patients, which is what we as clinicians are most interested in,” explains Citrome.
The researchers found that when duloxetine was compared with placebo using data from the two FDA approval studies, the NNT was found to be six. This low NNT supports the case for such a treatment approach. This finding also compared favorably with other studies of NSAIDs over 13 weeks – the NNT was five for etodolac after 4 weeks and four for tenoxicam after 8 weeks.
The studies used to gain FDA approval also showed that pain reduction using duloxetine on its own was not dependent on an improvement in depressive symptoms.
“Although the use of duloxetine as a monotherapy for pain has been approved by the regulatory agencies, it is quite common for patients to receive a combination of drugs, and NSAIDs are the most frequently prescribed drugs for the pain associated with osteoarthritis,” explains coauthor Amy Weiss-Citrome, a specialist in Physical Medicine and Rehabilitation.
As a result, the authors also examined the findings of a recent study that showed the potential synergy of duloxetine and NSAIDs.
In the 10-week double-blind trial of 524 patients with osteoarthritis of the knee, those administered with a combination of duloxetine and NSAIDs reported greater pain reductions than the control group, who took a NSAID with placebo.
The NNT for the outcome of substantial improvement in pain with combination treatment versus NSAIDs alone was six, supporting the benefits of this approach.
“We believe that our analysis of these studies demonstrate that clinicians managing patients suffering from osteoarthritis should also consider prescribing adjunctive antidepressants that can effectively impact on central pain pathways,” concludes Citrome.
– Written by Paolo Reveglia
Source: Citrome L, Weiss-Citrome A. Antidepressants and the relief of osteoarthritic pain – findings from a study examining adjunctive duloxetine. Int. J. Clin. Pract. 66(5), 431–433 (2012).
Recent research published in the Proceedings of the National Academy of Sciences has discovered that an inflammatory response can be seen in the brain as a result of activation of a brain immune receptor by certain opioid drugs, including morphine.
Morphine is a widely used and important drug used for relief of pain, however, users can experience several different side effects, including a higher sensitivity to pain and the build up of tolerance to morphine.
Mark Hutchinson (University of Adelaide School of Medical Sciences, Australia) explains, “For some time it‘s been assumed that the inflammatory response from morphine was being caused via the classical opioid receptors. However, we found instead that morphine binds to an immune receptor complex called Toll-like receptor 4 (TLR4), and importantly, this occurs in a very similar way to how this receptor detects bacteria.”
Investigators were also able to show how the immune receptor located in the brain can be blocked. This could be a pivotal discovery in finding novel drug therapies, that can not only enhance the efficacy of morphine, but also lessen many of morphine‘s unwanted side effects.
Hutchinson states, “Our experiments in mice have shown that if this relationship with the immune system receptor is disrupted, it will prevent the inflammatory response.” He continues, “This is an exciting result because it opens up possibilities for future drugs that promote the beneficial actions of morphine while negating some of the harmful side effects. This could lead to major advances in patient and palliative care.”
During their experiments, the researchers were able to specifically show that morphine binds to myeloid differentiation protein 2 – which is an accessory protein of TLR4. This then induces TLR4 oligomerization and trigger proinflammation. The authors write that disrupting the TLR4–myeloid differentiation protein–protein association “potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro,” and that this latter observation shows that proinflammation induced by morphine is dependent only on TLR4, “despite the presence of opioid receptors.”
Regarding the impact of the research, Hutchinson explains, “Because morphine is considered to be such an important drug in the management of moderate-to-severe pain in patients right around the world, we believe these results will have far-reaching benefits.”
– Written by Roshaine Gunawardana
Sources: Wang X, Loram LC, Ramos K et al. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc. Natl Acad. Sci. USA 109(16), 6325–6330 (2012); The University of Adelaide News and Events: www.adelaide.edu.au/news/news51801.html
Chronic pain is a major challenge to treat as understanding pain is very important in the development of new therapies. There is variability in the development of chronic pain between people with the same disorder, which raises the need for individualized treatments that can treat specific patient groups.
Research by Jeffrey Mogill (McGill University, Montreal, Canada) and colleagues published recently in Nature used genome-wide linkage analysis to identify a major gene that plays a part in pain sensitivity. They identified the P2X7 gene, which affects chronic pain via both inflammation and nerve damage. Researchers found an association between nerve injury-induced pain behavior and P451L mutation of the P2X7 receptor. This mutation caused impaired pore formation of the receptor. The single amino acid change affected the formation of the pore, which allows large molecules to pass through.
The investigators found that administration of the peptide that affects the P2X7 receptor C-terminal domain by blocking the pore formation only and not any other function of the gene (e.g., cation channel activity, caused the reduction of pain-related behaviors).
The genetic differences between two independent human cohorts, one with chronic post-mastectomy pain and the other with osteoarthritis, were assessed and it was found that the people with a genetic susceptibility to low pore formation in P2X7 experienced lower levels of pain.
These findings suggest that drugs could be developed that block pores at this crucial receptor, leaving others intact to kill pain, with a lower side-effect profile as only one function of the gene will be impaired. This research could lead to a new strategy of individualizing the treatment of chronic pain.
– Written by Claire Attwood
Source: Sorge RE, Tang T, Dorfman R et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat. Med. 18(4), 595–599 (2012).
Researchers have demonstrated, in a report published in Neuroscience, that it could be possible to develop treatment options that can protect infants from adverse effects experienced through anesthesia.
General anesthesia has been shown to be potentially harmful to very young children in recent studies. These studies specifically demonstrate that general anesthetic use on young children “can promote learning deficits as they mature.”
Investigators looked into several different methods to try and defend against damage to the infants‘ brain induced by anesthesia. In their study, researchers used postnatal day 7 rats, and these rats were injected with either ‘vehicle‘ – a sterile phosphate-buffered saline solution, or ketamine – a NMDA receptor antagonist and a popular general anesthetic.
Results showed that levels of proapoptotic enzyme AC3 were increased in rats treated with (toxic dose) ketamine. Additionally, it was observed that levels of activity-dependent neuroprotective protein (ADNP) was also increased.
Investigators were then able to demonstrate that by injecting the postnatal day 7 rats with a specific ADNP peptide fragment 15 min prior to ketamine injection, the injury could be reversed in a dose-dependent fashion.
Furthermore, it was demonstrated that “ketamine-induced apoptosis” at postnatal day 7 could be prevented by treating postnatal day 6 rats with a specific dose of vitamin D3, or a specific nontoxic dose of ketamine.
Conversely, the authors write that when postnatal day 7 rats were pretreated with a particular level of aspirin 15 min prior to administration of ketamine, levels of AC3 were seen to be increased in certain regions.
Christopher Turner (Wake Forest University School of Medicine, NC, USA) states “What didn‘t work was aspirin, which was a surprise because aspirin is known to protect the brain from injury. In fact, in our study aspirin actually increased the severity of injury from the anesthesia, possibly because it prevents the generation of substances that may be neuroprotective.”
The results of the experiments highlight the possibility that there are several different techniques that could be used to combat infant brain injury induced by anesthesia.
Turner explains, “We designed our studies to give doctors several possible treatment options because not all of these strategies may work in clinical applications. However, because vitamin D3 is already in clinical use, our findings show that it is quite promising with few risks. Further, NAP is currently in clinical trials to diminish the severity of other types of brain injury, so we feel this discovery represents a breakthrough for anesthesia-induced neurotoxicity.” He warns that “there may be a critical window of efficacy for NAP, which we need to explore further.”
In conclusion, Turner states, “Of all the approaches that our team studied, using a low dose of ketamine may be both the simplest and most cost effective, as it suggests that children can be pretreated with the same anesthesia that will be used when they undergo general surgery. In essence, a low-level dose of ketamine primes the child‘s brain so that the second, higher dose is not as lethal, much like an inoculation.”
– Written by Roshaine Gunawardana
Sources: Turner CP, Gutierrez S, Liu C et al. Strategies to defeat ketamine-induced neonatal brain injury. Neuroscience doi: 10.1016/j.neuroscience.2012.02.015 (2012) (Epub ahead of print); Wake Forest Baptist Medical Centre – News Releases: www.wakehealth.edu/News-Releases/2012/Treatments_to_Reduce_Anesthesia-Induced_Injury_in_Children_Show_Promise_in_Animal_Studies.htm
Chronic pain is one of the biggest causes of poor quality of life worldwide, with an estimated one in six Europeans suffering from long-term pain. Now a collaboration of German and Chinese scientists believe they may have found a new therapeutic target that could lead to more effective options for analgesia.
Chronic pain is often exacerbated by synaptic long-term potentiation (LTP), where the nerves transmitting pain signals to the brain become overactive. This leads to the pain hypersensitivity seen in painful pathologic conditions such as inflammation or nerve injury.
The team‘s aim was to build on previous work attempting to identify the signaling molecules involved in pain-related LTP. Previous studies suggested that the messenger, cyclic GMP, could be involved, so the researchers sought to identify a specific mechanism that could be the cause.
They found that PKG-1 played a key role in LTP of the nociceptor synapses. By generating knockout mouse models lacking PKG-1 in the presynaptic nociceptors of the spinal cord, the team could demonstrate that LTP was completely halted. In addition, the behavior of the mice changed dramatically, indicating a freedom from pain that could be traced straight back to PKG-1.
The team have high hopes for their finding and its potential as a therapeutic target. Publishing their findings in PLoS Biology, they write that “these results clarify basic mechanisms of pathological pain and pave the way for new therapeutic approaches.”
Their optimism will no doubt be shared by the millions of sufferers of chronic inflammatory pain.
– Written by Lucy Abel
Source: Luo C, Gangadharan V, Bali KK et al. Presynaptically localized cyclic GMP-dependent protein kinase 1 is a key determinant of spinal synaptic potentiation and pain hypersensitivity. PLoS Biol. 10(3), e1001283 (2012).