COX2 Inhibitors Unlikely to Help Visceral CP

Wow, it is so hard to get researchers to distinguish between the pains. So we are always relieved when they stop making everything a unity and begin threading out individual pains. Those with CP may have some or all of them and now we have some small information on visceral CP.

Cyclo-oxygenase2 (COX2) is an enzyme that converts prostaglandin precursors to prostaglandins. It is at the crossroads of inflammation and pain. For example, it is now known that a fertilized egg cannot implant in the uterine lining unless COX2 has caused inflammation in the lining. Both follicle stimulating hormone and gonadotrophins from the pituitary contribute to the formation of COX2 in the uterus. Pregnant women sometimes report being able to “feel” when they have implanted. Even more report a slight spotting at that time.

Chemicals including and similar to prostaglandins are thought to be sufficiently powerful to make non-uterine cells in the female pelvis turn into something resembling uterine lining, and may even occur on the bowel or remotely elsewhere. This condition is known as “endometriosis”, classically a painful pelvic condition. Endometriosis is probably present to some degree in half of all woman who reach age 32 without getting pregnant, the occasion of pregnancy tending to interrupt the cycling of prostaglandin impact on the pelvic lining. Prostaglandins apparently acidify the surface of the uterine lining, making it more penetrable by the egg. However, we are interested most here in how the prostaglandins affects Central Pain.

In nerve synapses, prostaglandins acidify the perineural environment, making the generation and propagation of pain signals more potent. It is not clear whether this “acidification” makes the synaptic surfaces more susceptible to neurotransmitters. Using “search” you can find extensive materials on prostaglandins and pain at this site. Cyclo-oxygenase inhibitors have often been prescribed for chronic pain although concerns about long term effects have led to restrictions on COX2 inhibitors to short term use.

The “viscera” include the esophagus, stomach, gut, bladder, and uterus. Willert, in conjunction with CJ Woolf (one of the premier pain researchers in the world), and others have shown in the August 2005 European Journal of Pain, that visceral pain is different. They used a model of central sensitization, NOT exactly the same thing as central pain, to show that cyclo-oxygenase2 is NOT involved in the spinal mechanisms that lead to visceral pain which is caused by central sensitization. We do not know all the molecular mechanisms involved, so making a clear distinction between central pain and central sensitization is not yet possible, but CP involves injury to the Central Nervous System, whereas central sensitization does not, at least no obvious injury. Central Sensitization probably results from some peripheral injury which keep the central pathways going, but may not involve production of fetal ion channels which increase the pain.

Although it is not really clear how much central sensitization teaches us about Central Pain, presumably similar mechanisms are involved. Central sensitization of the viscera (hollow organs like gut and bladder) causes secondary allodynia (see prior article explaining the differences between primary and secondary hyperalgesia). Allodynia is simply pain from nonpainful stimulus eg. touch, while hyperalgesia is greater than the expected amount of pain from a stimulus normally thought to be painful, eg. pin prick. Both indicate sensitization and heightened gene expression of pain exciters like MAPK (mitogen activated protein kinase). Dr. John Bonica who contributed to the early formation of the Wall/McHenry database on CP, felt that the hyperalgesia of Central Pain was so extreme that it should have its own term, so he preferred “hyperpathia”, as did Dr. Wall.

The reason why we find this article interesting is that many CP patients have visceral pain. It is about half in the gut and about half in the bladder. Pain is the esophagus is harder to pin down, but presumably some have nerve injury pain there as well in CP, since gastroesophageal central sensitization is considered not uncommon. Central sensitization probably hooks into some of the pathways of CP, at least temporarily. Central sensitization (CS) is not overpowering like CP so the level of sensitization is somehow less, but don’t tell anyone with central sensitization that their pain is “less” since it really devils them and they can spend a fortune trying to get rid of it. It is a mystery to us that more have not used resiniferatoxin on the CS illnesses. It is already used in central senssitization of the bladder (irritable bladder) with success, so we are anxious to see how destruction of the TPRV-1 channel affects the evoking aspect of Central Pain.

It can be observed in Alan Hess’s “Central Pain Update III” (the number one most read article at this site) that visceral central pain can be very severe. Valdecoxib, a cyclooxygenase inhibitor (COX2 inhibitor) did not help the centrally sensitized, so it is unlikely to be of help to those with CP visceral pain.

This study, which was deemed important enough to attract Woolf’s participation, does indeed suggest that Central Pain is the Central Pain(s). We already knew this from the surveys, but it shows why the condition presents differently and responds differently. The day may not be too far off when resiniferatoxin can be infused into the gut to kill all receptors that would add to the evocation of central pain. This does NOT mean that the spontanaous pains will be helped, but it is possible. Weir Mitchell showed long ago that in nerve injury pain to peripheral nerves, pain from touch or evocation is instantaneous; whereas, in pain of central origin, the evocation needs at least twenty seconds to get going. The diagnosis and separation between the two types of nerve injury pain, central and peripheral, can be reliably achieved using Mitchell’s delay. In the case of gut and bladder pain, however, it is not so easy since infusion and distention takes time. However, most with visceral CP THINK that there may be some delay. For example, bladder filling must reach some small degree before it is perceived, although this may merely represent a threshold, rather than a true delay. We will watch future studies with interest. About one third of CP subjects have some visceral pain, but it is really severe in no more than 15%.

When present, visceral CP is very difficult. It can mean one never confidently leaves the house, or at least cannot go far, for fear that unbearable pain may suddenly come on.

We thank Willert and his colleagues and hope they will continue to thread this thing out.