Ketamine’s antidepressive effects
tied to opioid system in brain
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In a new analysis published Wednesday in the journal Scientific Reports, UC San Diego researchers said millions of FDA side effect records reveal that people who took ketamine for pain relief reported lower rates of depression.
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“The occurrence of complaints about depression dropped in half after ketamine administration,” said UC San Diego Skaggs School of Pharmacy professor Ruben Abagyan, who led the study.
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The researchers focussed on the FDA’s Adverse Effect Reporting System, a database that tracks negative side effects among people who take various drugs. But the researchers were not primarily interested in bad outcomes.
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Instead, they looked for a positive outcome: declining rates of depression among people taking drugs not typically thought of as antidepressants.
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They found signs that other common drugs — including Botox, a pain reliever called diclofenac and the antibiotic minocycline — also reduced depression among patients in the FDA database.
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[minocycline is a glial modulator and it can prevent CRPS from spreading.]
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University of Miami psychiatry professor Charles Nemeroff wrote that the study was, “very interesting.”
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“The findings are of considerable interest. However the interpretation of the findings are key,” he wrote, saying it will be important to understand whether ketamine is directly treating depression or simply relieving pain, which can indirectly help people experience less depression.
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The UC San Diego researchers said they controlled for this variable by comparing people who took ketamine with those who took other pain medications. They said they still found a larger drop in depression among those who took ketamine.
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Critical thinking is not a partisan issue. Tens of millions will lose jobs as robots rapidly take over in the next 3 years. Industry will reap more than ever in history. We all need to rethink our lives at some point.
Advertising signs that con you
Into thinking you’re the one
That can do what’s never been done
That can win what’s never been won
Meantime life outside goes on
All around you.
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Tools |
# of Items |
Administered |
Patients considered for long-term opioid therapy: |
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ORT Opioid Risk Tool |
5 |
By patient |
SOAPP® Screener & Opioid Assessment for Patients w/ Pain |
24, 14, & 5 |
By patient |
DIRE Diagnosis, Intractability, Risk, & Efficacy Score |
7 |
By clinician |
Characterize misuse once opioid treatments begins: |
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PMQ Pain Medication Questionnaire |
26 |
By patient |
COMM Current Opioid Misuse Measure |
17 |
By patient |
PDUQ Prescription Drug Use Questionnaire |
40 |
By clinician |
Not specific to pain populations: |
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CAGE-AID Cut Down, Annoyed, Guilty, Eye-Opener Tool, Adjusted to Include Drugs |
4 |
By clinician |
RAFFT Relax, Alone, Friends, Family, Trouble |
5 |
By patient |
DAST Drug Abuse Screening Test |
28 |
By patient |
SBIRT Screening, Brief Intervention, & Referral to Treatment |
Varies |
By clinician
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METHODS: Major databases, including MEDLINE, EMBASE, Cochrane, and Scopus, were searched through October 2014, for studies reporting the role of ketamine in the treatment of bipolar depression. Only randomized controlled trials were included in the meta-analysis. We calculated standardized mean differences (SMDs) with SE for each study included in the meta-analysis. A random effect model was used to calculate the pooled SMDs. Heterogeneity was assessed using the Cochran Q test and I statistic.
RESULTS: Of the 721 articles that were screened, 5 studies that enrolled a total of 125 subjects with bipolar depression (mean age, 44.6+/-4.3y and 65.6% females) were included in the systematic review; 3 randomized controlled trials (69 subjects) were included in the meta-analysis. The meta-analysis showed significant improvement in depression among patients receiving a single dose of intravenous ketamine compared with those who received placebo (SMD=-1.01; 95% confidence interval, -1.37, -0.66; P<0.0001). The maximum improvement was observed 40 minutes after the ketamine infusion. No heterogeneity was observed between the studies (Cochran Q test P=0.38, I=0%). The 2 studies that were excluded from the meta-analysis also showed significant improvement in depression after ketamine therapy. Individual studies also reported improvement in anhedonia and suicidal ideation after ketamine therapy. None of the subjects had serious side effects, and the side effects were similar between the ketamine and placebo groups.
CONCLUSIONS: This study suggests that ketamine is effective in treatment-resistant bipolar depression and may reduce suicidal ideation and anhedonia.
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snip
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The material on this site is for informational purposes only, and
is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
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For My Home Page, click here: Welcome to my Weblog on Pain Management!
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Ketamine daily TID did nothing for migraine, but continuing it at 80 mg TID for weeks – perhaps 2 months, migraine GONE first time in 20 years, for > 2 or 3 months. No sx of migraine at all
then added naltrexone 4.5 mg and triggered migraine!
Stopped LDN couple days, and he had a couple migraine even after stopping, now none for couple weeks again, on ketamine.
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The material on this site is for informational purposes only.
It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
Relevant comments are welcome.
If any questions, please schedule an appointment with my office.
This site is not for email.
~~~~~
For My Home Page, click here: Welcome to my Weblog on Pain Management!
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F R Carreno, J J Donegan, A M Boley, A Shah, M DeGuzman, A Frazer and D J Lodge
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This is an excellent model for studying Alzheimers Dementia and may explain why my patient with Alzheimers has been so stable for so many years. Yale with NIMH had published that ketamine rapidly creates synapses, that led to treating a senior with Alzheimers. This should encourage further research on memory and dementias.
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The material on this site is for informational purposes only.
It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
Relevant comments are welcome.
If any questions, please schedule an appointment with my office.
This site is not for email.
~~~~~
For My Home Page, click here: Welcome to my Weblog on Pain Management!
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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.
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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
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This site is not for email and not for appointments.
If you wish an appointment, please telephone the office to schedule.
~~~~~
For My Home Page, click here: Welcome to my Weblog on Pain Management!
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Please ignore the ads below. They are not from me.
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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.
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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
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This site is not for email and not for appointments.
If you wish an appointment, please telephone the office to schedule.
~~~~~
For My Home Page, click here: Welcome to my Weblog on Pain Management!
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Please ignore the ads below. They are not from me.
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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.
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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
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This site is not for email and not for appointments.
If you wish an appointment, please telephone the office to schedule.
~~~~~
For My Home Page, click here: Welcome to my Weblog on Pain Management!
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Please ignore the ads below. They are not from me.
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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.
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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
This site is not for email and not for appointments.
If you wish an appointment, please telephone the office to schedule.
~~~~~
For My Home Page, click here: Welcome to my Weblog on Pain Management!
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Please ignore the ads below. They are not from me.
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>>
PUBLIC WARNING
The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.
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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
This site is not for email and not for appointments.
If you wish an appointment, please telephone the office to schedule.
~~~~~
For My Home Page, click here: Welcome to my Weblog on Pain Management!
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Please ignore the ads below. They are not from me.
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Psychiatrists from Mt. Sinai in New York this month have published the first randomized controlled trial of intranasal ketamine showing it is safe, well tolerated, and rapidly effective in treating symptoms of depression in persons with Major Depressive Disorder.
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This is a small study of 18 patients with treatment resistant depression showing a significant antidepressant effect occurred as early as 40 minutes in some. 44% responded after 24 hours compared to 6% placebo. Ketamine was significantly different from placebo at 40 minutes, 240 minutes, and 48 hours, but not separable from placebo at 72 hours or 7 days thought they were still better. And ketamine was significant at improving anxiety symptoms at 24 hours. There were no clinically significant changes in heart rate or blood pressure and all changes resolved in four hours. “No serious adverse events occurred.”
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“Intranasal ketamine was well tolerated with only very minimal increases in dissociation, psychosis-like symptoms or hemodynamic parameters.” They felt these very minimal behavioral side effects and insignificant changes in blood pressure and pulse were consistent with the lower blood levels of ketamine compared to the higher doses used in studies of IV ketamine. Bioavailability via intranasal route is reported to range from 25% to 50%.
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Their sample had an average of 4.1 ± 3.9 treatment failures, compared to 5.7 and 5.1 in previous studies – those required a minimum of 2 to 3 treatment failures to enroll. Other clinical characteristics did not differ including “duration of illness, length of current depressive episode, and history of ECT.” They allowed ongoing treatment of psychotropic medication.
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They chose a 50 mg dose based on a previous study and on the dose used in persons with a chronic pain disorder (Daniel Carr, et al 2004). It is a lower dose than the 0.5 mg/kg dosage commonly given intravenously. They point out one limitation of the study was the use of the single dose and a standardized protocol, which did not allow them to study optimal dosing. Future study is needed to address optimal dosing, relapse prevention and scheduling of treatment.
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The minimal side effects shown in their study correlates well with my experience. I find the effective dose of ketamine is idiosyncratic. That means it is unpredictable and specific only to that individual. Large males may need only the smallest dose, and tiny elderly females may require far higher doses. That may account for the higher response rate that I believe I am seeing, however, I have not tracked percentage of responders. I have not seen toxicity in years of prescribing either for intractable pain or treatment resistant depression. Importantly, in my opinion, relapse prevention must address not only different neurotransmitters but also neuroinflammation, pro-inflammatory cytokines.
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The material on this site is for informational purposes only.
It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
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For My Home Page, click here: Welcome to my Weblog on Pain Management!
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The material on this site is for informational purposes only.
It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
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For My Home Page, click here: Welcome to my Weblog on Pain Management!
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Stress and depression leads to structural changes in the brain and these structural changes are reversible.
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Depression affects 17% of the population, almost one in five of the population. Only one third of patients are effectively treated by existing antidepressants, even after many weeks. Nerve growth factors, in particular BDNF, are decreased by stress, with a very significant loss in depressed patients. BDNF produces antidepressant behavior in rodent models of depression.
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BDNF is important for influencing the survival and function of neurons.
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There are certain neurogenic zones in the brain that produce new neurons. Stress decreases the number of new neurons. Chronic antidepressant use increases the numbers and proliferation of these new neurons. Antidepressant treatment increases neurogenesis and this is dependent upon BDNF, this neurotrophic factor.
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[His slide shows] Exercise, Prozac, ECT, antipsychotics, antidepressants increase neurogenesis.
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Not only are there more synapses made by ketamine, but they are a larger size which is indicative of ones that are more functionally connected. Antidepressants take many weeks. A single dose of ketamine rapidly reverses depressive behaviors and loss of connections and completely reverses the decrements that had occurred over several weeks.
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In suicidal patients given ketamine at Yale in the Emergency Room, within a matter of hours, the suicidality is completely reversed. These people are better for weeks after a single dose of ketamine treatment. [emphasis mine]
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Therapeutically ketamine is even more rapidly acting than ECT.
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Sierra wildflowers
Click to embiggen
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This is a very bright young woman who was an all state volleyball player until onset of Complex Regional Pain Syndrome three years ago in the right hand and wrist. It began after blood was drawn from the hand for a chemistry study and, one week later, the fingers turned black, lost blood flow, followed by emergency surgery for removal of a blood clot from the back of her hand. She woke after surgery, tearing the sheet off due to intense pain on light touch — that is called allodynia — and then developed severe edema from the hand to the shoulder.
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This happens so often. This is 2012.
If it’s not the doctors,
it’s the insurance companies
creating roadblocks to diagnosis or treatment or both.
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Why is pain management not taught at medical schools?
Only 3% of schools today give 30 hours instruction in four years, Yale most recently.
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At a major university hospital two hours away, she failed to respond to 14 stellate and brachial plexus blocks. But the wound reopened by itself, the stitch fell out. The psychiatry department evaluated her after she was so drugged with methadone, she does not even recall the interview. They diagnosed Munchausen Syndrome. That changed everything. Relationship went sour. Distrust of MD’s began and was confirmed many times in many places along the northeastern corridor and Texas.
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That fall, she became a student at the university of her dreams. The diagnosis of CRPS was confirmed at their university medical center hospital where they wanted to continue the same blocks that had failed. Elsewhere, the chief of a renowned ivy league university pain service wanted to talk to her only about spinal cord stimulators, declined by the family.
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In May 2010, she qualified for an NIH study of neurotropin double blind 6 weeks on, 6 weeks placebo. Failed.
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She was seen by Dr. Schwartzman in Philadelphia October 2011, and sent from there to NYC to rule out neuroma dorsum right hand, negative.
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On Lyrica, she gained 20 lbs, then back to 130 lbs baseline when off of Lyrica. Intolerance to Morphine – hives, Duragesic – total body itching. Ambien – hallucinations, Lunesta – hyper. Benadryl helped somewhat. Detoxing from Nucynta – lips were bright red.
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Her weight dropped from 130 to 115. Many medications were trialed and failed. Marinol helps pain slightly and gives the best sleep in years, better appetite. It does cause anxiety, but she had not slept in three years, and it gives 4 to 6 hours of good sleep. She developed sharp bitemporal headaches. I advised headache is a side effect of Pristiq —- now thankfully discontinued and better.
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Since August 2011, she has had CRPS pain in the right leg, worse walking, weight bearing. There is discoloration of the dorsum hand usually, at times along proximal forearm, recently at right foot and leg. She had edema up to the shoulder measuring 30 cm. Nails growth faster at the right hand, possibly less hair growth right hand. Temperature usually cooler on the right hand, at times at night the hand and foot become hotter. No change in sweating noted.
The first year, she had almost total loss of function in the hand with pain and contractures —and forced herself to move the fingers with OT and PT, then home exercise. She still has days when the fingers remain flexed, but 98% of the time there is full movement as she continually tries to use the hand/fingers to write and type. Nose may become ice cold and tingly since CRPS spread to right side of face and right lower limb. At times tingling fingers. She struggles with memory when pain is severe and with lack of sleep.
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Pain ranges 7 to 10, average 8. Edema was significant for one year, now comes and goes. Allodynia is present hands and feet, now a different scale than before when she could not even be in the car.
However, with weight bearing and walking, pain of the right lower limb became most intense. She will be 21 in July, but on a bad day was unable to leave her bedroom to walk downstairs as pain was too severe. She would communicate with family by loudly calling or texting. It was unthinkable to make plans for the next week due to severe pain. She has osteoporosis with atrophy of the right upper limb, and has had color changes and edema of the hand.
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She lives in an eastern state inland, two hours away from the mid Atlantic seaboard and major medical center. She failed ketamine infusion at a major university medical center on the east coast. The cost and inconvenience was significant and the family did not know that ketamine may fail to have any effect if taking opioid analgesics. Once mom discovered that, she was able to wean off the opioid medication. Ultimately, after many more interventions, much later, in crisis, she did benefit from IV ketamine infusion, and was able to regain some movement of her fingers on the right hand, but there was no lasting relief. It was a struggle to obtain approval through her insurance.
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She has been spending a great deal of time in bed for months. Morning stiffness is widespread for one to two hours. Bending is difficult, feels as if “hit by a bus,” but she does stretching, moving, distraction and Yoga when able.
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Day one: pain of the entire right side, face, trunk, limbs, rated 7 to 10 on a scale of 10, average 8. She guards the dominant right hand and the signature is difficult. Atrophy of the right upper limb is present, nails longer on the right hand, dusky dark erythema and long jagged scar over the dorsum right hand, mild erythema of the right upper and right lower limbs.
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On the first day, in the office, she tried the first dose of ketamine nasal spray and after a repeat dose, she was puzzled, thinking to herself, then let us know she realized she was able to concentrate. A small dose is not enough to relieve severe pain, but even major depression can vanish at that dose. Two sprays relieved the brain fog of depression; pain was still 8 on a scale of 10. Blood pressure and pulse did not change before and after doses. She felt hopeful.
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In the next few days she was able to do the unthinkable: make plans with friends, walk 45 minutes, become active, and remain active in a way that had not been possible. She was far more active with much less pain. Over the weekend, six days after she arrived, after we had sequentially added several new medications, she found the dosage of nasal and sublingual ketamine that worked for her. She has actually had times when she was pain free. As noted during prior ketamine infusions, she requires a far higher dose than most patients to achieve effect. The plan now is to use higher doses at home when time permits for best effect, and booster sprays of nasal ketamine as needed when away from home. She can carry it in her pocket. There is no need for ICU infusions and the fight to get insurance coverage for those stays.
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Of great significance, she has even made plans for the entire summer.
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More details of her case will be added, as time permits. For now, this page is here to allow the patient and family and others to send comments. She will continue slow titration of other medications that will take three months before reaching the target dose, before we can assess efficacy. Based on my experience treating chronic intractable neuropathic pain including CRPS, it is possible these medications will be able to stabilize and relieve pain without ketamine.
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See other case reports of treatment of CRPS here, here, and here.
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You can read some of the science of pain, glia and inflammation. Ketamine is significantly anti-inflammatory. Three of her new medications are glial modulators. Treatment of severe chronic pain usually involves rational polypharmacy, not one medication and not medication alone. It requires a holistic approach to heal: P.T., O.T., massage, cognitive behavioral therapy, guided imagery, visualization, positive thinking, remaining active, and other modalities that depend upon the underlying cause: physical, emotional, spiritual, and financial. The treatment for CRPS is not specific for that condition alone, but the gains can be possible with tremendous discipline, effort, single minded determination and the loving support of friends and family.
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Be cautious of spinal cord stimulators. Try everything else first.
They can create pain and scarring or tether the spinal cord.
Be proactive.
Remember that guidelines and strategies for diagnosis and treatment are outdated.
Support RSDSA.org if you can.
They support high quality pain research.
You can go directly to their site or donate to them (not me)
using the link at the top of my site here.
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Patients and doctors do not understand that opioids create pain.
A 2006 publication from Vanderbilt shows how much better pain can be to taper off.
The abstract:
Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.
The article:
Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.
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More on this young woman’s journey coming.
It’s been busy!
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