Summary: Gut microbiota plays a crucial role in human health, especially in the treatment of complex regional pain syndrome and pancreatic pain. Any alterations in gut microbiota can increase the risk of various health disorders, including these two conditions. However, to date, there is limited understanding of gut microbiota, and there are no reliable tests to measure changes in the gut microbiota. A new study shows that almost 58% of the variance in plasma metabolites can be explained with the help of variance in the gut microbiota population. Thus, it is pretty likely that we may see the introduction of blood tests to understand changes in gut microbiota.
There are more than 100 trillion microorganisms living in the human gut. Yet, it is unbelievable how little we know about them. It is beyond doubt that they are not parasites but rather living in symbiosis. It is a mutually beneficial relationship between humans and microorganisms.
Over time, the human body has evolved to become dependent on these microscopic unicellular beings for its well-being. For example, they help train human immunity and provide vitamins, neurotransmitters, and various bioactive compounds. Studies show that any disruption in the population of gut microbiota leads to various health disorders, including complex regional pain syndrome and pancreatic pain. Changes in gut microbiota are associated with not just gastrointestinal problems but also various metabolic health issues. In addition, Dysbiosis even increases the risk of mental health issues.
Though there are many studies showings that changes in gut microbiota cause health disorders, there is one significant problem. Science still does not know what makes healthy gut microbiota. The reason science does not understand healthy microbiota is due to the massive diversity of the gut microbiota population. These are bacteria and fungi belonging to various classes, order, and species.
However, untangling this puzzle is essential if we want to understand the human body fully. Understanding the gut microbiota and its role in health would help us prevent various health disorders and even treat health conditions. Of course, it does not mean that we do not know anything about them. We do know a lot, but it is still the tip of the iceberg. Science knows that bacteria like lactobacillus are good for health.
There are many challenges in understanding the role of gut bacteria. Firstly, we need to understand what makes this massive population fully. Secondly, we need to understand what kind of nutrients and bioactive compounds they produce. At present, we only know that the total population of these microorganisms in the gut is in trillions, and they probably produce hundreds of beneficial bioactive compounds.
However, science is fast making progress in understanding the role of gut microbiota in health. Science already knows much about the metabolites produced by gut microbiota. In the new study of 8583 participants aged 50 to 64, researchers could find that about 58% variance of individual plasma metabolites was associated with gut microbiota population diversity. These numbers are massive. It shows that gut microbiota can significantly influence various body functions by making changes to these plasma metabolites. It appears that gut microbiota has a greater say in our health than imagined earlier.
Further, by understanding how changes in various plasma metabolites are associated with changes in gut microbiota, we can better manage health conditions and understand changes in the gut microbiota.
Till now, the main way of studying the gut microbiota population is through microbiological studies of gut tissue or fecal material. However, it appears that by analyzing plasma metabolites, we can also understand much about gut microbiota. Moreover, these findings are clinically relevant since plasma tests for various metabolites are much easier to carry out than microbiological studies of gut tissues.
Hence, it is pretty likely that in the future, we may see blood tests that would be able to provide precise information about changes in the gut microbiota, help treat health conditions due to these changes, and even monitor the treatments.
Covid has already affected more than 600 million people. Fortunately, more than 99% have made a recovery from acute illness. Unfortunately, however, a considerable number of people failed to make a complete recovery. An estimated 10-20% who had Covid infection continue to experience fatigue, lack of mental focus, body aches, and other symptoms. It is a condition called long Covid. What is worrisome is that doctors still lack an understanding of long Covid. Despite this, there are treatment options available, including physical therapy and medications, as well as interventional procedures such as complex regional pain syndrome treatment.
The covid pandemic is still ongoing. It has affected more than 600 million adults and resulted in more than 6.5 million fatalities. Those are massive numbers. However, what is worrisome is that though more than 99% have made a complete recovery, they are still not feeling well. Many are still living with constant fatigue, lack of focus, and other health problems. Something doctors are now calling long Covid. The number of people living with long Covid is massive. The WHO estimates that anywhere between 10-20% of those affected by the coronavirus infection are living with long covid. These individuals feel fatigued, lack focus, are anxious, and often lack mental clarity. Many may also report body aches. For many, the condition is so debilitating that they have to leave their jobs and stay at home.
One of the biggest challenges that doctors face is that they know very little about the condition. They do not understand why post-Covid syndrome lasts so long in some individuals. They feel helpless as they do not have answers to many questions. Most lab tests are close to normal in people living with long Covid and chronic pain. Thus, lab diagnostics aren’t of much value in the condition. However, long Covid cannot be neglected. One cannot say that it is merely a psychological issue in some. Observations show that long Covid must be taken seriously. Many people are living with long Covid experience exacerbation of various health disorders.
Clinical studies now also confirm that long Covid must be taken seriously, as people living with the condition are more likely to die prematurely. Studies suggest that the risk of premature death in those living with long Covid is almost twice higher than those who made a complete recovery. This is a significant difference.
There are multiple reasons why doctors find it so challenging to diagnose the condition. Not only are there no reliable lab tests, but there are no symptoms specific to the condition. In addition, it means that every patient living with long covid differs from another. For some, significant fatigue may be the primary concern. For others lack of mental focus.
Nonetheless, health experts have noticed that fatigue is one of the most significant concerns. It is present in most cases. It means that people living with long Covid struggle to stay physically and mentally active. However, one can guess that fatigue is relatively common in many health conditions. Additionally, doctors find themselves helpless when fatigue is the prime complaint in the absence of other signs.
However, it does not mean there is no progress in understanding long Covid. Researchers have already found some early evidence. One study found that coronavirus spike protein, used to diagnose acute infection, is present in small amounts even after complete recovery. Spike protein can be traced even one year after recovery. This spike protein might be causing inflammation and chronic fatigue.
However, to date, researchers have not been able to conclude what causes long Covid. Some other health experts suggest that the condition may occur due to tiny blood clots. Moreover, cardiovascular issues post-Covid are pretty common. Since the condition is poorly understood, patients are unsure of where to seek treatment. Thus, some are treated by physicians, others by psychiatrists. However, it appears that pain medicine specialists may also help in many instances, especially when chronic body pains and fatigue are primary complaints.
Summary: Osteoarthritis of finger joints is a highly debilitating condition. Pharmacological drugs can provide pain relief in the condition, but they are unsuitable for preventing disease progression. Thus, patients have to take medications daily. Now a new study shows that injecting fat tissues into the finger joints may provide prolonged relief. Furthermore, these fat tissues are extracted from the patient’s other body parts, making the treatment a highly safe procedure.
Osteoarthritis is the leading cause of joint pains. It is a disease of wear and tear that especially affects weight-bearing joints like knees and hips. The disease is more likely to occur in those living with some inherent weaknesses, metabolic disorders, and more. Most people diagnosed with the condition are middle-aged or older adults. Though osteoarthritis in fingers is relatively less common, it is not uncommon.
Since osteoarthritis is a disease of older adults and a wear and tear condition, it is difficult to treat. The changes that have occurred in the joints are almost irreversible. It means people affected by the condition must live with the pain lifelong. Chronic pain associated with joint disorders may be quite debilitating.
Osteoarthritis progresses slowly over the years. Though the condition may not be reversible, doctors can treat and provide chronic pain relief associated with the condition. However, most people will have to take non-steroidal anti-inflammatory drugs daily.
Taking daily painkillers helps, but it is not easy to use medications daily. Moreover, pharmacological drugs may cause many side effects.Therefore, researchers experimented with a new kind of safe and minimally invasive treatment: lipofilling. It is a procedure in which doctors inject a patient’s own fatty tissues inside the joints. Then, they retrieve these fatty tissues using liposuction from other body parts like the upper thighs.
The procedure is safe as doctors inject a minute amount of fatty tissue into the joint. They inject merely one milliliter of fatty tissue into the arthritic finger joint. In the new study, researchers found that this simple procedure was amazingly effective, providing almost instant relief. Patients had to wear a splint and take painkillers for a week, and after this, they experienced profound relief. Moreover, the procedure did not cause any complications.
The present study was done in 25 finger joints. Researchers regularly followed up with the patients for 44 months, paying particular attention to pain scores. Researchers say that the benefit from the treatment was significant.
Before treatment, patients had a pain score of 6 out of ten, and after treatment the pain score was merely 0.5, which is just a mild sense of discomfort. Researchers say that they have been amazed by such results. Moreover, the treatment was especially good for reducing pain scores.
Additionally, the patient also demonstrated improvement in joint health and functioning. For example, their pinch grip strength almost doubled from a median of 2 kg to 4.3 kg. This is a massive difference. It means that treatment not only provided pain relief but also enhanced the functionality and quality of life of people living with chronic pain due to finger osteoarthritis.
In recent years, lipofilling has gained significant popularity. It is especially used in various cosmetics and reconstructive procedures. Lipofilling is so good for osteoarthritis as it may help reverse the disease process. Animal studies show that these fat cells are rich in mesenchymal stromal cells (kind of stem cells). Thus, lipofilling promotes tissue regeneration in arthritic joints.
However, researchers admit that they still need to carry out more studies to understand the benefits of such a treatment fully. For example, they need to carry out studies using control groups. Additionally, they also need to understand the long-term benefits of such a treatment.
Nonetheless, there is no doubt that this treatment is highly promising. It is minimally invasive, safe, and easy to carry out, but it helps preserve the joint structure and promote regenerative processes. Therefore, many people living with chronic pain due to osteoarthritis may expect a benefit from such treatment. In addition, it may help them start living without their daily dose of painkillers.
The Takeaway
While mentioning chronic pain, it might not be a mere discomfort, rather a complex underlying medical ailment that calls for a specialist treatment. Hence, Padda Institute of Pain management offers a comprehensive complex regional pain syndrome treatment to suit your needs. Schedule your appointment today and get immediate chronic pain relief.
Summary: All pain societies in the US have recently updated their guidelines for managing cervical spine joint pain. They have made similar recommendations to end the confusion and standardize treatment for the condition. The new guidelines recommend that all patients with cervical spine joint pain undergo radiological examination. Unlike older recommendations saying that RF ablation may be considered if two nerve blocks provided more than 80% pain relief. The new guidelines state that a single nerve block providing more significant than 50% pain relief is sufficient for considering RF nerve ablation.
Cervical spine joint pain or chronic neck pain is quite common. Moreover, it propagates, causing shoulder pain and even headache. Managing such pains requires prolonged use of medication and even the use of surgical interventions. Unlike medications, surgical interventions may pose a greater health threat. However, such invasive interventions may also provide permanent pain relief in many instances. Thus, one may be able to live without medications.
However, there is another important and minimally invasive procedure that is less risky and may still provide permanent pain relief, like surgical interventions. This method is called radiofrequency (RF) ablation of the cervical medial branch. Simply speaking, in the procedure, doctors use radio waves to inactivate the nerve, prevent pain propagation and thus prolong relief.
Though RF ablation may sound good due to its safety and efficacy, not everyone may benefit from this procedure. Though there have been many guidelines regarding when to use RF ablation in patients presenting with cervical pain, all pain societies in the US recently updated their guidelines simultaneously. This will help end the confusion and ensure that all pain specialists use a similar kind of treatment approach for the condition1,2.
When using RF to disable the nerve permanently, doctors use certain methods to ensure that they are selecting the right nerve and that disabling that nerve will help the patient. Thus, before RF ablation, they would carry out nerve block or facet block using medications. This procedure is reversible. Hence, if a nerve block worked for a patient and helped reduce pain, it means that such a patient can be considered for RF nerve ablation, resulting in permanent disabling of the nerve and, thus, pain relief. This entire procedure of Facet Joint Radiofrequency has shown some promising results in managing spine joint pain.
These standardized guidelines made multiple changes to ensure patient safety and improve cervical spine joint pain treatment. For many doctors, it may be a surprise that the new guideline recommends radiological imaging before considering facet block. The guidelines say that such an assessment does not play many roles in diagnosing the condition and in its prognosis. However, radiological assessment is good for safety and procedural planning.
Another exciting and significant recommendation is regarding the number of nerve blocks to carry out before going for RF nerve ablation. Early recommendations were that doctors carry out at least two nerve blocks, which must provide 80% or more pain relief. Only then may a patient be considered for RF nerve ablation.
However, now these recommendations have been changed significantly. The new recommendations say that just a single nerve block providing pain relief greater than 50% is enough to move forward with RF nerve ablation. This recommendation is significant, as doctors think that in cervical pain the facet joint is a more significant pain generator. It means that those living with cervical spinal pain are more likely to benefit from Facet Joint Radiofrequency.
Facet joint injection is a similar kind of early intervention that can help reduce opioid dependency, as many of those living with chronic cervical pain need to use these medications. Experts say that they have made these recommendations since their findings show that RF nerve ablation has better outcomes for cervical spine joint pain compared to lumbar pain or low back pain.
These guidelines would have many implications. First, it would help standardize cervical spine joint pain and sciatica nerve pain treatment. Earlier, there were multiple guidelines with different recommendations. Since now all guidelines make similar kinds of recommendations for treating the condition, it would help reduce confusion, which is good for patients. Of course, it is worth knowing that the final decision is always made by treating doctors, as they are in the best position to decide if any procedure will work for a given patient.
The standardization of guidelines would have other benefits for patients, like they are now more likely to be covered by insurance since all guidelines have similar kinds of recommendations. But, of course, these guidelines are not constant, and they may change in the future as medicine is always progressing.
Padda Institute of Pain Management has a proven record of spine joint pain and sciatica nerve pain treatment with its uniquely created facet joint radiofrequency treatment. Get in touch with our specialists to get pain relief.
Summary: Complex regional pain syndrome (CRPS) is among the most difficult-to-treat conditions causing chronic pain and increased sensitivity to various stimuli. Even slight exposure to some irritants may cause severe pain. Thus, the condition is debilitating. In 2018, Johnathan H. Goree, MD, proposed the treatment protocol for the condition. In the new study, researchers validated the protocol and found it quite effective in Complex Regional Pain Syndrome treatment and in reducing allodynia. Some pains are quite challenging to treat, causing allodynia, a condition when even some common irritants that generally do not cause pain may cause severe pain in such individuals. One such example of a chronic and painful condition with a reduced pain threshold is complex regional pain syndrome (CRPS). CRPS remains quite a poorly understood condition, as its pathogenesis is unclear. Nonetheless, there has been much progress in new treatments for CRPS over the years. Moreover, many doctors and pain specialists now realize it as a distinct pathological condition requiring a specific treatment approach. In 2018, Johnathan H. Goree, MD, develope`d a treatment protocol for CRPS. This treatment protocol recommends using gabapentin, bisphosphonates, ketamine, stellate ganglion blocks, and neuromodulation through occupational therapy, and it also recommends quitting smoking. Although this protocol was produced after years of research, in medicine, any protocol can only be widely accepted if it has been validated in multiple studies and in different population groups2. After all, any treatment recommendation is of little value if its results cannot be repeated in different clinical settings. Furthermore, there is always a risk that the person who created the protocol missed something. However, now, a new study shows that this treatment protocol works. The protocol was validated in an independent study by Mi Mi Kim, M.D., M.P.H., Loren Guzman, M.D., and Johnathan Goree, M.D. from the Department of Anesthesiology, University of Arkansas Medical Sciences, Little Rock, AR. They shared the findings of their study at a 19th Annual Pain Medicine Meeting. The treatment protocol consists of four primary areas of focus; pain management, sympathetic nerve block, occupational therapy, and smoking cessation. In the study, patients received 300 mg gabapentin thrice daily, 35 mg alendronate daily, 10% topical ketamine, and some other painkillers like tramadol. For nerve blockers, they mainly used bupivacaine plus epinephrine. After one month of treatment, most patients reported significant benefits in treating CRPS symptoms. Those who reported significant benefits continued with home-based therapy and occupational therapy. The therapy was repeated in the patients who responded to treatment in the early stages but stopped responding later. The study involved 25 patients, and all reported significant benefits. In addition, the benefit was proportional to therapy adherence. 40% of the participants in the study reported significantly improved range of motion. However, this improvement was close to 85% in patients with better adherence to the therapy. Similarly, 60% of patients reported reduced allodynia. Again, this improvement was barely 11% in those with poor treatment adherence but above 80% in those with more or less good treatment adherence. The researchers found that bisphosphonate use and stellate ganglion blocks highly correlated to reported benefits. They also noted that issues like depression, anxiety, and opioid use in the initial presentation did not make a difference in the final outcomes. This means that this treatment protocol is good for different kinds of patients. In short, the study could validate the proposed treatment protocol for CRPS. It found that benefit from the treatment protocol was significant only if patients adhered to the prescribed treatment. Moreover, the study also found that even those with moderate adherence benefited significantly. Only those with very poor adherence did not report any benefit. CRPS is among the most challenging-to-treat conditions causing chronic pain and reduced pain threshold. The pain is debilitating in most cases, and patients do not respond to the most commonly used pain treatments. Thus, this new treatment protocol offers hope.
Read more about how we approach ketamine for RSD and CRPS at the Padda Institute, including candidacy, monitoring and the off-label status of this use.
Summary: Intractable pain is among the most challenging pain syndromes to treat. Quite often, doctors need to prescribe opioids to manage such pain. However, opioids cause many side effects. It now appears that one of the drugs used to treat substance abuse, Naltrexone, is quite good for managing intractable pain and works at a low dose. Moreover, low-dose naltrexone (LDN) therapy works even better when used with other drugs like anti-inflammatory medications and drugs used to treat neuropathic pain. However, its concurrent use with opioids is not recommended due to severe side effects or interaction risk.
Among chronic pains, nothing is more challenging to treat than intractable pain. As the name suggests, it is not just pain but a condition that is challenging to treat with traditional painkillers. People living with intractable pain continue to experience pain, even when the condition that caused pain initially has been cured. Doctors do not fully understand why some people continue to experience intractable pain. However, they think such pain occurs due to neuroinflammation, spinal inflammation, and changes in certain brain centers.
Hence, intractable pain requires quite a different treatment approach compared to pains that occur due to other reasons like low back pain, arthritis, or rheumatological conditions. However, very few options currently exist to provide satisfactory relief for intractable pain. That is why regulatory agencies in some US states have identified intractable pain as a distinct kind of health problem that is different from chronic pain and a condition that justifies prolonged opioid therapy.
However, issues related to prolonged opioid use are not a secret. First, people become addicted to these drugs. Not only that, these drugs cause hyperalgesia, and thus people need to increase their dose over time, further increasing the risk of side effects. However, it appears that researchers have now identified a novel way to manage intractable pain. Using low-dose Naltrexone (LDN) is one of the emerging therapies for intractable and chronic pain treatment.
Naltrexone is an old and well-known medication used to treat substance abuse, and it is also good for treating opioid abuse and even reversing some of the side effects of opioids. However, now researchers have found that when used at lower dosages, it can be an excellent painkiller that also helps lower inflammation of spinal and brain tissues and even boost immunity.
This use of LDN to manage intractable pain is still an off-label use. It means the US FDA has still not approved it for such use. Nonetheless, its use is justified due to its excellent safety profile. Moreover, the clinical safety of the drug is well established. The only limitation of this drug is that it should not be used along with opioids since it would reduce the impact of opioids and may have certain unpleasant interactions with these drugs.
Doctors generally use 0.5 to 1 milligrams of Naltrexone medication twice daily to manage intractable pain. Using LDN may help intractable pain without the need for opioids. It seems that LDN is good to use along with other medications like gabapentin used for neuropathic pains, Adderall, Mucuna, and other medications. Doctors may also recommend Naltrexone (LDN) for pain relief along with standard anti-inflammatory medications like ketorolac.
LDN can have significant results in case of complex regional pain syndrome (CRPS) treatment and sciatica nerve pain relief. It appears that LDN is quite beneficial when used consistently for a long period, along with other less toxic painkillers. In addition, unlike other drugs, LDN has the ability to modulate intractable pain by altering immune responses and reducing neuro-inflammation. Thus, in the long run, it may help achieve complete remission of intractable pain.
As already mentioned, it is not good to use opioids, as it can interact with these medications in an unpleasant way. However, doctors may use synthetic opioids in a low dose during pain flares. Though, its long-term use, along with high-dose opioids, is not recommended due to the risk of some severe side effects. Those taking opioids can also be switched to LDN therapy. However, such patients would first need to discontinue opioid use. Studies show that some patients may become severely ill if they take LDN while using opioids.
Since LDN is still an experimental therapy, researchers say that if a person is experiencing satisfactory pain relief from opioids, then there is no reason to switch to LDN.
Summary: Chronic pain is among the most common comorbidities in those being treated for opioid use disorder (OUD). However, a new study found that in most cases, doctors treating OUD do not pay sufficient attention to chronic pain management, resulting in higher opioid relapse. They also found that those treated with medications like methadone or buprenorphine had better pain relief and, thus, better treatment outcomes. Therefore, researchers recommend that doctors focus on managing comorbidities when treating OUD.
When we think of people living with OUD, we completely neglect that many of them live with severe chronic pain such as, neck pain, complex regional pain syndrome, etc. This poorly managed chronic pain may be related to poor treatment outcomes in many. Studies show that chronic pain is the most common comorbid condition in those living with OUD. Recently, the Journal of Pain published a patient survey, finding that two-thirds of those treated for OUD reported that their chronic pain was not managed well. Even worse, 47% reported that their pain worsened over time, thus increasing the risk of opioid relapse. The opioid crisis continues to be a significant health problem, and it is showing no sign of slowing down. Moreover, the coronavirus pandemic only increased opioid use disorder (OUD) and drug overdose-related deaths. This only underlines the need to pay more attention to the effective opioid addiction treatment.
Health experts say that the problem in tackling the opioid crisis is not just in lack of access to opioid treatment, which is true. Still, other factors make treatment more difficult and result in high relapse rates. In addition, most people treated with OUD have other comorbidities, with many living with mental health issues and chronic pain. Although it is no secret that chronic pain and OUD are related health issues. However, it is unknown how ill-managed pain in those living with OUD may affect treatment outcomes for the condition. Health experts say that one of the problems is that treating doctors focus significantly on OUD, but less on comorbidities, especially issues like chronic pain.
In the new survey, researchers analyzed the data of 14,449 patients getting treated in 225 OUD treatment centers. They found that one-third of all the patients had significant chronic pain. Out of these patients, just one-third reported that their chronic pain was managed properly with pharmaceutical drugs. Moreover, almost half of all the patients said the pain was the primary reason for opioid relapse. Researchers say this is a massive sample size, and they were amazed to see that so many patients are not being treated adequately for their chronic pain. Many of these patients have even used street drugs like heroin to manage their pain.
When researchers interacted with doctors treating OUD, they were often told that treating pain was not their priority or not within the scope of their practice. Researchers say that there is a need to understand that pain is among the most significant causes of opioid relapse. Hence, effective treatment of OUD must include adequate pain relief. The study had another unexpected finding related to opioid relapse. In the survey, 20% of those treated for OUD said that they would return to opioid use once they overcame their addiction. It means that treatments are not preparing them well for post-treatment life, and many of them still view opioid use as an option.
The study also found that those treated with OUD with medications had a higher success rate. Thus, those treated with buprenorphine and methadone reported better treatment satisfaction. It seems that one of the reasons for a greater success rate with these medications is that they also help with chronic pain treatment. Thus, health experts say addiction treatment will only improve if different health specialists work together. Moreover, the coronavirus pandemic has shown that interdisciplinary collaboration using technologies like telemedicine is not that difficult.
Of course, researchers say that the study has also raised certain questions, like the role of opioids in pain management. As a result, the researchers suggest that the use of opioids for managing chronic pain should be limited. Additionally, researchers say that one of the issues is that doctors often do not view chronic pain as one of the significant issues. They forget that this pain may be due to comorbidities like depression and mood disorders requiring treatment. If these comorbidities remain unmanaged, relapse is more likely.
Hence, researchers concluded that OUD should be treated by multi-specialist teams, including pain management, psychiatry, psychology, integrative medicine, and physical therapy. In addition, we should treat the patient as a whole and not merely focus on reducing pain numbers on a scale.
Ketamine may help with chronic pain because it blocks the NMDA receptor, a glutamate receptor in the spinal cord and brain that keeps pain circuits amplified long after the original injury has healed. It is not an opioid and does not act on opioid receptors. It works on the amplifier rather than the volume knob, which is why it is considered mainly for pain that has become centrally driven rather than pain from an ongoing structural problem.
That is the theory. The evidence is narrower: the best trials are in complex regional pain syndrome (CRPS, also called RSD), the effects are modest and often temporary, and a 2025 Cochrane review of 67 randomized trials rated the certainty of evidence across chronic pain as a whole low to very low.6
Ketamine is an anesthetic. At full doses it produces dissociative anesthesia; at the far lower doses used in pain medicine — often a tenth or less of that — it produces analgesia while the patient stays awake and conversational. Its primary action is non-competitive antagonism at the NMDA receptor. It has no affinity for GABA receptors, which separates it from sedatives and benzodiazepines. The liver converts it into norketamine,1 which is itself an NMDA receptor antagonist.10 In the United States it is a Schedule III controlled substance, FDA-approved as an anesthetic; use for chronic pain is off-label and governed by specialty consensus rather than by a label.2
When a peripheral nerve fires repeatedly, second-order neurons in the dorsal horn of the spinal cord respond more strongly to each identical input. This is wind-up, and the NMDA receptor is central to it. At rest the channel is plugged by a magnesium ion; sustained depolarization expels the magnesium, the channel opens, and calcium flows in, triggering changes that make the neuron more excitable and keep it that way.
Scale that up and you get central sensitization — the nervous system amplifying signals out of proportion to the input. Clinically it looks like allodynia (pain from a bedsheet or a breeze), hyperalgesia, and pain spreading beyond the original injury. Once that state is established, treating the tissue does not necessarily fix the pain, because the pain has stopped tracking it.
CRPS is where this argument is strongest. Clinical and experimental evidence implicate NMDA receptor activity and glial activation in how CRPS is induced and maintained.4 If the receptor is doing the maintaining, blocking it should do more than mask pain — it should let the sensitized circuit reset.
There is some evidence for that. Pharmacokinetic-pharmacodynamic modeling in 60 CRPS-1 patients found analgesia persisting well after ketamine had cleared the plasma, with an estimated onset/offset half-life of about 11 days; the authors read this as ketamine initiating a cascade of desensitization in excitatory receptor systems that slowly abated.5 Relief that decays over weeks rather than hours would separate ketamine from an ordinary analgesic — but that reading rests on a model fitted to a single trial, not on a replicated finding.
In the foundational trial, 60 patients with CRPS-1 and a median disease duration of 7.4 years received a 4.2-day intravenous S(+)-ketamine infusion or placebo. Pain scores over 12 weeks were significantly lower with ketamine, and the lowest score came at the end of week 1 (2.68 versus 5.45 on a 0-10 scale). By week 12 the difference was no longer significant, and there was no functional improvement in either group. Psychomimetic side effects occurred in 76% of the ketamine group versus 18% of placebo.3 A second double-blind trial dosed four hours daily for ten days, capped at 0.35 mg/kg/h, and reported significant reductions across many pain parameters with none in the placebo group; both arms also received clonidine and midazolam, so the comparison is ketamine-plus-adjuncts against adjuncts alone.4
Now the counterweight. A 2022 meta-analysis of 20 randomized trials in 818 adults with CRPS-1 found ketamine reduced pain by about 8 points on a 0-100 scale, while bisphosphonates reduced it by about 24; the authors’ first-line recommendation was bisphosphonates.7 Note the base the ketamine number rests on: only 2 of those 20 trials tested ketamine, against 7 for bisphosphonates. A systematic review concluded evidence for ketamine is emerging and confirmatory trials are still needed.8
Broadest of all, the 2025 Cochrane review pooled 67 randomized trials of NMDA antagonists in chronic non-cancer, non-headache pain. It found no clear evidence that intravenous ketamine reduces pain intensity in the immediate, short, or medium term, rated that evidence low to very low certainty, and found it may increase adverse events.6 Most underlying studies were small, and blinding is hard when three quarters of the treatment group can tell they got something.
The reasonable reading: ketamine is a legitimate option for severe, centrally driven pain that has failed better-established treatments, but the effect is modest and time-limited, and anyone presenting it as a general answer for chronic pain is ahead of the data.
“Ketamine therapy” means at least three treatments with different pharmacology, evidence, and risk.
IV delivery bypasses first-pass metabolism, so plasma levels are predictable and can be titrated in real time against effect and side effects. This is the route used in nearly all the controlled trials, and where the evidence lives. It requires monitored administration, because the same dose control that makes it effective makes it possible to overshoot.
Swallowed ketamine is heavily metabolized before reaching the circulation. A lozenge study in six chronic pain patients — the authors called the findings preliminary — measured median bioavailability of 24% by both oral and sublingual routes, with extensive first-pass conversion to norketamine.10 A larger population pharmacokinetic study of a 50 mg S-ketamine oral thin film in 20 volunteers found bioavailability of about 26%, with roughly 80% converted to norketamine.11
That conversion is not purely a loss, since norketamine is an active NMDA antagonist. The sublingual route gives a different exposure profile rather than a simply weaker one: less parent drug, more active metabolite, a flatter curve. Note what those studies do and do not show — they measure how much drug reaches the blood, not whether the pain improves. On that second question the Cochrane review found no clear benefit for oral ketamine.6
Topical ketamine is the outlier, because it may not be working centrally at all. In a double-blind placebo-controlled crossover trial, 10% ketamine cream applied to the affected limb of 20 CRPS patients inhibited allodynia to light brushing and hyperalgesia to punctate stimulation, while plasma ketamine stayed below detectable limits — implying a peripheral action at cutaneous nociceptors. Touch thresholds were unchanged: it reduced the abnormal amplification without numbing the skin.9
That is a mechanistically interesting result from one small crossover study, and it should be read against the pooled evidence. The same Cochrane review found no clear evidence that topical ketamine reduces pain intensity in the immediate or short term, at low to very low certainty.6
Sublingual and topical formulations can be applied to a defined limb or taken at home without the infrastructure an infusion requires, which is why they get used outside research settings. That is a practical argument, not an evidence-based one. Route selection remains clinical judgment, not a settled question.
A subanesthetic infusion is given with the patient awake and monitored. Blood pressure and heart rate typically rise, since ketamine stimulates the sympathetic nervous system. Patients commonly experience some mix of dissociation, visual distortion, dizziness, nausea, and detachment; these track the dose and clear with the drug. Consensus guidelines note that adverse events in most trials were few, but that higher doses and more frequent infusions carry more risk.2
Two harms are tied to repetition rather than a single exposure. Repeated prolonged infusions have caused drug-induced liver injury: in one series, three of six CRPS-1 patients receiving a second 100-hour infusion 16 days after the first developed elevated liver enzymes, which normalized within two months after stopping.12 Sustained heavy exposure — documented mainly in recreational users — can produce ulcerative cystitis and bladder fibrosis, with contracted bladder and hydronephrosis in long-term abusers.13 New urinary urgency, frequency, or pelvic pain during a course is a reason to stop and be evaluated, not to push through.
The consensus guidelines list a set of relative contraindications — situations calling for caution or avoidance rather than absolute prohibition: poorly controlled cardiovascular disease, severe liver disease, certain poorly controlled psychoses, elevated intracranial or intraocular pressure, pregnancy, and active substance abuse.2 A pharmacology review states plainly that long-term analgesic effects in chronic pain have not been demonstrated and that long-term safety questions remain unresolved.1
The CRPS trial that produced significant pain relief produced no functional improvement3 — pain came down and the limb did not start working better on its own. That is the argument for treating a course as a window rather than a destination: it can lower the pain floor enough to make graded movement tolerable, and rehabilitation is what changes function. In CRPS, meta-analytic evidence favors bisphosphonates first,7 and sympathetic blockade, stellate ganglion blocks, and spinal cord stimulation each have their place. Ketamine belongs in the conversation after simpler options, not instead of them.
Padda Institute, Center for Interventional Pain Management, provides intravenous ketamine infusion as well as sublingual and topical formulations, with route chosen by diagnosis and tolerance. See ketamine therapy and complex regional pain syndrome treatment. Dr. Gurpreet Singh Padda, MD, MBA, MHP practices at 4477 Woodson Rd, Suite 100, St. Louis, MO 63134 and 12174 Natural Bridge Rd, St. Louis, MO 63044. Phone: (314) 481-5000.
No. In the strongest CRPS trial the difference from placebo faded by week 12, and function did not improve.3 Where it helps, it lowers pain for a period measured in weeks rather than permanently, which can create room for rehabilitation — one option among several under pain treatments.
No. Its primary action is blockade of the NMDA glutamate receptor, not activation of opioid receptors.1 It is a controlled substance and requires the same care as any controlled medication, but it is a different pharmacologic class from opioid analgesics. See the pain management physicians page.
It varies widely and is not predictable in an individual. Modeling in CRPS-1 patients estimated an onset/offset half-life of roughly 11 days, with relief outlasting the treatment period.5 Some patients get weeks; some get very little. The decision to continue is made against measured response — part of the evaluation under CRPS treatment.
They are not equivalent, and not simply weaker versions of one thing. Sublingual bioavailability is roughly a quarter of the dose taken, with most of the rest converted to norketamine.1011 Topical ketamine appears to act peripherally on the skin, with plasma levels too low to measure.9 Both have a thinner evidence base than infusion: pooled analysis found no clear benefit for either oral or topical ketamine.6 They are used because they are practical for a defined limb or for home dosing; see ketamine therapy.
No. Subanesthetic infusions are given with the patient awake and monitored, not under general anesthesia. Dissociative effects are common and dose-related, and resolve as the drug clears.3 Arrange for someone else to drive. The same awake, monitored approach applies to other procedures here, including nerve blocks.
For CRPS, meta-analytic evidence favors bisphosphonates first,7 and sympathetic blockade has its own supporting trials.8 Depending on the pain generator, an epidural steroid injection may be more appropriate. Start with a diagnosis-first evaluation: request an appointment or use the contact page.
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