When people are dealing with persistent pelvic pain (or any type of persistent pain), often times they are truly willing to try many different treatment approaches to seek relief. While we tend to recommend the most conservative treatments possible (such as Pelvic PT , exercise, and minimally invasive medical strategies), some people find that they still want to add additional types of treatments to their care. There are numerous interventions out there such as nerve blocks, Botox injections, pulsed radio frequency ablation, cryoablation, and Ketamine infusions. We hope to address all of these topics, as many of our followers seek out this information. If I can impart one important piece of information it is this: Pain is complex and individual. There is not one best treatment for pain. Outcomes are best when patients (and family members) are actively involved versus ONLY receiving passive modalities (medications, massage, injections, etc).  The topic of Ketamine infusions can elicit some strong concerns. Some clinicians are familiar with a type of infusion known as “Ketamine comas,” in which people are placed in a medical coma and stay in an ICU for treatment. This is often viewed as quite extreme, and risky; and leaves many wondering the efficacy of such a treatment when the patient is not actively participating in recovery from a brain/pain connection. For clarification, the coma is not the only protocol available. Ketamine infusions can involve: 1. Outpatient “awake” protocol 2. Low-dose inpatient protocol 3. Ketamine coma. (In addition, there are now physicians who prescribe compounded ointments with Ketamine as one of the medications. This is not the same as an infusion. There’s not enough data at this time about efficacy and safety of this approach with topicals.) Our guest blogger, Dr. Allison Wells, MD, is sharing information about the outpatient procedure.  ~ Tracy Sher of Pelvic Guru

Ketamine as a Treatment Option for Chronic Pelvic Pain

Chronic pelvic pain can have links to anatomical pain generators and mood disorders like depression and anxiety. In some cases, pelvic pain can have an inciting trauma that precedes the pain and can possibly cause PTSD as well. To effectively relieve chronic pelvic pain, a treatment that addresses all those issues is ideal: Ketamine infusions may be that treatment. 

Pain, PTSD, and depression can certainly go hand in hand. Being in horrific, constant, endless pain can cause depression, PTSD and anxiety. And having depression and anxiety can worsen the perception of chronic pain.  For example, patients with complex regional pain syndrome (CRPS) are much more likely to also have a mood disorder than the general population.

Ketamine was discovered in the 1960s and has been used for anesthesia safely for more than 50 years. Since the 1980s ketamine has been studied and used as a rapid-acting and effective treatment for mood disorders, working in hours instead of weeks like SSRIs. Also, ketamine may restore a sense of joy in life, a symptom that often isn’t relieved by traditional anti-depressant medications. Ketamine has well-known analgesic and local anesthetic properties.  Ketamine possibly works through downregulating GABA-A or NMDA receptors that have been up-regulated and become self-sustaining in the pain syndrome.

Ketamine has several sites of action. It works at the opioid receptors and local anesthetic receptors in the periphery. It also works on NMDA, AMPA and norepinephrine receptors in the central nervous system after pain has been centralized. Two completely distinct actions at two separate sites. 

Ketamine is very useful for patients with PTSD. Many patients with CRPS have PTSD from either the original inciting injury or from all the trauma of daily life in agony. Ketamine is very helpful for PTSD, but it is also helpful for painful neurological conditions unrelated to PTSD – like post-stroke pain, cancer pain, endometriosis, diabetic neuralgia.

Intravenous infusion therapy is used in most treatment protocols studying ketamine for the relief of neuropathic pain syndromes. Other delivery methods, such as oral delivery, are generally less favorable. The drug is unpredictable when taken by mouth as it is metabolized and broken down by the liver after absorption from the intestinal tract before it can have its effect on the nerves it’s meant to treat. Also, most studies appear to indicate that ketamine concentrations need to reach a certain threshold and stay steadily above that threshold for a few hours to accomplish the resetting of the pain receptors. Intravenous therapies provide this steady state- which doesn’t necessarily happen with single oral, intranasal or IM dosing as the dose can’t be titrated to effect once given. Initially, ketamine comas were induced using high doses (7-9mg/kg/hr) over many days. Ketamine comas had to be done in the ICU with a breathing tube and specialized nursing care. They entailed a high risk of blood clots and liver dysfunction, and patients had muscle breakdown and weakness from the week of immobilization. Lower dose, (20mg/hr) continuous infusions were also used as the induced coma fell out of favor. Patients received lower doses and didn’t need a breathing tube, but patients did have to remain in the hospital for many days. Medicine has moved away from inpatient treatments: day surgery and outpatient surgery are recognized as much more cost-effective and they allow the patients more freedom in the comfort of their own homes. In the last decade, researchers realized outpatient infusions were almost as effective and much more practical. Now, a common dosing regimen is moderate sedation for a few hours at a time. These infusions use a moderate dose – much higher than the low dose inpatient therapy, but lower than the coma dose (2mg/kg/hr)– for only about 4 hours a day for several days closely spaced. Most side effects of the medication are well-tolerated and last only as long as the infusion. Hallucinations and feelings of dissociation are generally mild and may be treated. Sleepiness is common. In clinically useful doses it is not considered physically addictive. The beneficial effects of ketamine can last for weeks or months and follow-up treatments can help maintain the effects. Europe has been using ketamine infusions to treat chronic pain and depression as part of standard practice. In America, ketamine is not FDA approved for the treatment of pain and depression because there have been no large randomized controlled trials. It is really hard to randomize patients in a ketamine trial – they know immediately whether they were given the control or the active medication. Also, who is going to pay for such a trial when there is no readily apparent way to profit off a generic drug that can’t be patented? For this reason, ketamine is considered “off-label” and insurance companies consider it experimental and most do not pay for it outside of a few pain therapy programs linked to large tertiary care medical centers like: Stanford Medical School, Baylor College of Medicine, and Icahn Mount Sinai School of Medicine. Some physicians across the country are offering treatments on a cash-pay basis. In Summary: Ketamine infusions are generally considered experimental, but results of studies to date show good results, and it may be an excellent option for patients with severe, intractable neuropathic pain, especially those with mood disorders and trauma involved. Some research studies may be available for patients and there are some clinics providing treatments. ~Allison Wells, MD. ** Addendum on 5/21/16: I asked some follow-up questions based on some questions people have been asking since this blog article was posted.

PG: The concern is that patients will rush out to get Ketamine treatments without being fully evaluated for differential diagnoses and appropriate care with a team approach. How do you feel about that? Dr. Allison Wells (AW): “I don’t think in any way ketamine is appropriate without a complete diagnosis (and referrals are almost universally required by ketamine clinics) and trying other modalities both before and continuing PT and other treatments through care. But, for truly refractory patients (with a diagnosis, who’ve tried everything else) ketamine can help them on their way to recovery.” PG: The title of this article seems quite scary to many. Is this truly a risk or is this something most patients would not have to be concerned about? Excessive Ketamine Abuse Causes Bladder Cells To Commit Suicide AW: “People who use ketamine daily in high doses (street doses usually are GRAMS we use milligram dosing even for the highest infusion rates) can have bladder problems. This is almost never seen in clinical doses, and is in fact rare enough to be reported in journals when it has happened. The two case reports I was able to find involved patients developing urinary urgency and cystitis on very high doses of ketamine given for long-term infusions and when the doses were decreased or stopped the symptoms resolved.

People can, of course, use ketamine illegally as a street drug to try to medicate themselves. But this has serious and dangerous drawbacks. Ketamine is a tremendously safe drug and overdoses are very rare which is why it is so effectively used in operating rooms and battle fields all over the world. Street drugs are rarely pure and often what they are altered with can be toxic substances like talc or other drugs. Combining ketamine with other drugs can increase the likelihood of side effects like respiratory depression with opioids and elevations in blood pressure and heart rate with cocaine and speed. Hallucinations that ketamine can cause can be increased and made worse with combinations of LSD, PCP and ecstasy. Ketamine can cause heart arrhythmias and elevations in blood pressure that can lead to strokes which is why we use EKG monitoring and I recommend only to have these infusions monitored by anesthesiologists and not nurses who do not have the knowledge or authority to treat these possible complications.

Hallucinations can be severe with higher doses of ketamine- we can treat those with sedatives to alleviate the negative visions, if present. Patients are in a safe monitored environment and sent home with a trusted support person. This is very different from taking a street drug by yourself or without proper support. Ketamine received lots of negative press in the 1990s before it was made into a scheduled drug during the War on Drugs because it was being used as a date rape drug because while under the influence patients are very suggestible and compliant.”

Allison Wells, MD Board Certified Anesthesiologist Trained at Harvard’s Brigham and Women’s Hospital Anesthesiology Residency and Baylor College Of Medicine Lone Star Infusion, PLLC www.lonestarinfusion.com For more information and education on chronic pelvic pain solutions, check out Tracy Sher’s Puendal Neuralgia and Complex Pelvic Pain online and self-paced course! References Ketamine Advocacy Network Pain Physician. 2013 Jul-Aug;16(4):291-308. Central sensitization in urogynecological chronic pelvic pain: a systematic literature review. Kaya S1, Hermans L, Willems T, Roussel N, Meeus M. Clin Obstet Gynecol. 2003 Dec;46(4):797-803. Chronic pelvic pain as a form of complex regional pain syndrome.Janicki TI1. Psychosom Med. 1998 May-Jun;60(3):309-18. Abuse-related posttraumatic stress disorder and alterations of the hypothalamic-pituitary-adrenal axis in women with chronic pelvic pain. Heim C1, Ehlert U, Hanker JP, Hellhammer DH. T.E. Nolan, W.P. Metheny, R.P. Smith. Unrecognized association of sleep disorders and depression with chronic pelvic pain.  South Med J. 1992;85:1181-1183 EAU Guidelines on Chronic Pelvic Pain. Pain Physician. 2005 Apr;8(2):175-9.Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Goldberg ME1, Domsky R, Scaringe D, Hirsh R, Dotson J, Sharaf I, Torjman MC, Schwartzman RJ.: M. Falla *, A.P. Baranowskib, C.J. Fowlerb, V. Lepinardc, J.G. Malone-Leed, E.J. Messelinke, F. Oberpenningf, J.L. Osborneg and S.. Schumacherh European Urology, January 2014 Pain Physician. 2005 Apr;8(2):175-9.Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome.Goldberg ME1, Domsky R, Scaringe D, Hirsh R, Dotson J, Sharaf I, Torjman MC, Schwartzman RJ. Pain Med. 2008 Nov;9(8):1173-201. doi: 10.1111/j.1526-4637.2007.00402.x. Epub 2008 Feb 5. Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study. Kiefer RT1, Rohr P, Ploppa A, Dieterich HJ, Grothusen J, Koffler S, Altemeyer KH, Unertl K, Schwartzman RJ. CNS Drugs. 2012 Mar 1;26(3):215-28. doi: 10.2165/11595200-000000000-00000.Efficacy and safety of ketamine in patients with complex regional pain syndrome: a systematic review. Azari P1, Lindsay DR, Briones D, Clarke C, Buchheit T, Pyati S. JAMA Psychiatry. 2014 Jun;71(6):681-8. doi: 10.1001/jamapsychiatry.2014.62.Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. Feder A1, Parides MK2, Murrough JW3, Perez AM4, Morgan JE1, Saxena S5, Kirkwood K2, Aan Het Rot M6, Lapidus KA3, Wan LB1, Iosifescu D3, Charney DS7. Front Neurosci. 2015 Jul 21;9:249. doi: 10.3389/fnins.2015.00249. eCollection 2015.Antidepressant mechanism of ketamine: perspective from preclinical studies. Scheuing L1, Chiu CT1, Liao HM1, Chuang DM1.