Opiates Create Pain – A New Pathway Mediated by Microglia

01/20/2013 — Nancy Sajben MD

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Though morphine and other opiates are the gold standard for producing analgesia, paradoxically they may create pain.

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The mechanism, a microglia-to-neuron pathway in the spinal cord, has now been discovered by Ferrini et al. It was published in the on-line edition of Nature Neuroscience: 

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“Morphine hyperalgesia gated through microglia-mediated

disruption of neuronal Cl− homeostasis.”

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Their research was reviewed January 8 in Medical News Today, exerpted below:

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….”Our research identifies a molecular pathway by which morphine can increase pain, and suggests potential new ways to make morphine effective for more patients,” says senior author Dr. Yves De Koninck, Professor at Université Laval in Quebec City. The team included researchers from The Hospital for Sick Children (SickKids) in Toronto, the Institut universitaire en santé mentale de Québec, the US and Italy.

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New pathway in pain management

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The research not only identifies a target pathway to suppress morphine-induced pain but teases apart the pain hypersensitivity caused by morphine from tolerance to morphine, two phenomena previously considered to be caused by the same mechanisms.

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“When morphine doesn’t reduce pain adequately the tendency is to increase the dosage. If a higher dosage produces pain relief, this is the classic picture of morphine tolerance, which is very well known. But sometimes increasing the morphine can, paradoxically, makes the pain worse,” explains co-author Dr. Michael Salter. Dr. Salter is Senior Scientist and Head of Neurosciences & Mental Health at SickKids, Professor of Physiology at University of Toronto, and Canada Research Chair in Neuroplasticity and Pain.

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“Pain experts have thought tolerance and hypersensitivity (or hyperalgesia) are simply different reflections of the same response,” says Dr. De Koninck, “but we discovered that cellular and signalling processes for morphine tolerance are very different from those of morphine-induced pain.”

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Dr. Salter adds, “We identified specialized cells – known as microglia – in the spinal cord as the culprit behind morphine-induced pain hypersensitivity. When morphine acts on certain receptors in microglia, it triggers the cascade of events that ultimately increase, rather than decrease, activity of the pain-transmitting nerve cells.”

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The researchers also identified the molecule responsible for this side effect of morphine. “It’s a protein called KCC2, which regulates the transport of chloride ions and the proper control of sensory signals to the brain,” explains Dr. De Koninck. “Morphine inhibits the activity of this protein, causing abnormal pain perception. By restoring normal KCC2 activity we could potentially prevent pain hypersensitivity.” Dr. De Koninck and researchers at Université Laval are testing new molecules capable of preserving KCC2 functions and thus preventing hyperalgesia.

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The KCC2 pathway appears to apply to short-term as well as to long-term morphine administration, says Dr. De Koninck. “Thus, we have the foundation for new strategies to improve the treatment of post-operative as well as chronic pain.”

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Dr. Salter adds, “Our discovery could have a major impact on individuals with various types of intractable pain, such as that associated with cancer or nerve damage, who have stopped morphine or other opiate medications because of pain hypersensitivity.”

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Cost of pain

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Pain has been labelled the silent health crisis, afflicting tens of millions of people worldwide. Pain has a profound negative effect on the quality of human life. Pain affects nearly all aspects of human existence, with untreated or under-treated pain being the most common cause of disability. The Canadian Pain Society estimates that chronic pain affects at least one in five Canadians and costs Canada $55-60 billion per year, including health care expenses and lost productivity.

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“People with incapacitating pain may be left with no alternatives when our most powerful medications intensify their suffering,” says Dr. De Koninck, who is also Director of Cellular and Molecular Neuroscience at Institut universitaire en santé mentale de Québec.

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Dr. Salter adds, “Pain interferes with many aspects of an individual’s life. Too often, patients with chronic pain feel abandoned and stigmatized. Among the many burdens on individuals and their families, chronic pain is linked to increased risk of suicide. The burden of chronic pain affects children and teens as well as adults.” These risks affect individuals with many types of pain, ranging from migraine and carpel-tunnel syndrome to cancer, AIDS, diabetes, traumatic injuries, Parkinson’s disease and dozens of other conditions.”

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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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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Posted in Glia, Opioid Induced Hyperalgesia, Opioids, Paradoxical Pain. Tags: , . 2 Comments »

Ketamine IV vs Nasal Spray or Sublingual

08/22/2012 — Nancy Sajben MD

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Patients ask me to compare IV ketamine to other routes of administration such as intranasal or sublingual. No one has done comparisons. Even if they had, every person is different and may have several pain syndromes.

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I have outlined one case below. One disadvantage of IV ketamine is the cost and the need to schedule for an IV treatment with your physician often weeks in advance. For some, this may mean setting aside two weeks to travel and make other arrangements. The alternative is carrying this low cost medication in your pocket and using as needed to relieve pain when you have pain, or to prevent pain when you know your activity will flare it.

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Ketamine is an important medication for pain.  It is considered a third line choice for pain relief, but it is almost a first line choice for Complex Regional Pain Syndrome, CRPS  – the old term is RSD. And I prescribe it for other conditions that have been refractory to treatment. But, far more than any other pain syndrome, pain from CRPS can be flared by emotional stress or minor injury and it can spread to other areas.

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Ketamine is a short acting medication. It is both analgesic and anti-inflammatory.

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Opioids create pain; ketamine not only relieves pain, it also relieves inflammation. In fact, opioids may prevent ketamine from helping at all.

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A small number of pain specialists in the USA, most at university centers, provide IV ketamine for CRPS. Not all people respond. A lucky few may get months of pain relief, but may require monthly boosters, i.e. it may be a short acting medication only during the infusion or it may offer relief for weeks or months but not years. I do not believe anyone has published comparisons showing duration of effect.

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I view ketamine as a short acting medication that requires other combination medications to “clamp” the relief and prevent pain from recurring.

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Here is a case report posted a few years ago of my patient who had 8 months of relief from IV ketamine. It was given 24 hours/day for 5 days in May 2007, followed by four hour IV boosters two days every month. Unfortunately all ketamine stopped having any effect after 8 months. I then added multiple medications that were selected because of specific mechanisms — no opioids, no ketamine — and she has been pain free since December 2009 on a single drug.

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CASE REPORT

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Today was the 5th visit in the last two weeks with an out of state patient who has had CRPS since 1999. She also has sciatic neuropathy, chronic lumbar pain after 360 degree spinal fusion, shoulder pain, and two types of headache. Medications are now significantly helping all pain syndromes.

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Before seeing me, she had had a total of 9 infusions of IV ketamine most of them given at doses of 300mg/hr — a very high dose. She had no side effects from ketamine. One of those infusions was given for 6 days over 4 hours each day. She had failed a lidocaine infusion at high dose. A spinal cord stimulator was reprogrammed 10 times, but only made pain worse.

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I then started her on a combination of medications. With addition of the first new medication, she had 50% improvement in the first 24 to 36 hours, that lasted beyond the relief from nasal ketamine that was also started. Unfortunately, on day 8, she and another family member, came down with a virus that causes headache and severe vertigo. Nevertheless, all pain is markedly better.

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With ketamine she is able to reduce pain down to 1 on a scale of 10 for a few hours. Best of all she can carry it with her and use it as needed. She no longer needs to take two weeks out of her life to schedule IV ketamine infusions.

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It will take almost 3 months to slowly increase the other medications we started. Hopefully this combination will “clamp” the pain and prevent it from increasing so that she may become pain free without needing ketamine.

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After that, if she is able to become pain free, the plan is that we will then be able to slowly remove most of the new medications we started this week and still maintain relief of pain. I will see her again in the future.

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Sierra wildflowers

Click to embiggen

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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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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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Posted in Case Report, Complex Regional Pain Syndrome, Ketamine, Opioids, RSD, Sciatica, Spinal Cord Stimulator. Tags: , , , , , , . Leave a Comment »

RSD, Complex Regional Pain Syndrome – a case report

05/23/2012 — Nancy Sajben MD

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Severe Pain for Three Years,

 80% better in 10 days

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“This has been life altering.”

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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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It was four excruciating weeks before the diagnosis of complex regional pain syndrome was made.

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CRPS or RSD is a diagnosis that every MD,

every surgeon, every ER doctor,

every psychiatrist and psychologist, every nurse and therapist should know how to diagnose.

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Because she was a minor, they would not do nerve blocks.

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She developed contractures of the fingers and hand,

was unable to move the fingers.

  A major university hospital diagnosed Munchausen Syndrome;

mom was diagnosed with Munchausen’s by proxy.

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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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Much better in 10 days

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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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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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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, you will need to telephone my office.

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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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Posted in Case Report, Complex Regional Pain Syndrome, CRPS, Depression, Dextromethorphan, Glia, Ketamine, Lamotrigine, Low Dose Naltrexone LDN, Neuropathy, Opioids, Procedures, RSD, Spinal cord stimulators, Sympathetic blocks. Tags: , , , , , . 11 Comments »

Painkiller Efficacy in 2010 Less Than in 2000

01/28/2012 — Nancy Sajben MD

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This research shows efficacy of analgesics decreasing since 2000.

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“The evidence for pharmacological treatment of neuropathic pain” publication is a good meta-analysis of the current state of evidence-based treatment of neuropathic pain.

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I have quoted extensively from the article as it is important.

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“Abstract: One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients.”

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The black circles are recent circles, the light circles are from the past. Shift to the right means less effect.

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“Fig. 1. It shows the combined numbers needed to treat (NNT) values for various drug classes in all central and peripheral neuropathic pain conditions (not including trigeminal neuralgia). The figure illustrates the change from 2005 values in light grey to 2010 values in dark grey.  [emphasis mine]The circle sizes indicate the relative number of patients who received active treatment drugs in trials for which dichotomous data were available. Please note that the differences in study design and the patient populations preclude a direct comparison of NNT values across drug classes (see text). BTX-A: botulinum toxin type A; TCAs: tricyclic antidepressants; SNRIs: serotonin noradrenaline reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitor.”

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“Fig. 2. It shows the combined numbers needed to treat (NNT) values for different drug classes against specific disease etiologies. The symbol sizes indicate the relative number of patients who received active treatment drugs in the trials for which dichotomous data were available.”

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 A disease-based classification: fact or fiction?

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“Since (1) there are no clear indications that specific diseases should be treated with specific treatments, (2) symptoms and signs overlap in various neuropathic pain conditions [6], and (3) currently available drugs act with unspecific neurodepressant actions rather on pivotal pathophysiological mechanisms, at present there is no good rationale for a treatment algorithm that discriminates between underlying etiologies [45]. Nevertheless, the vast majority of trials have been done in painful diabetic neuropathy and PHN and few, if any, in certain other conditions (e.g. Guillain–Barré syndrome and small-fiber neuropathy), and recommending a treatment for other conditions may seem to be an unjustified jump.”

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“Supplementary Figure 1L’Abbé plot showing pain relief for all drugs for different neuropathic pain conditions. Each point illustrates one comparison against placebo (for trials listed in Supplementary Table 1). The axes indicate the percentage of patients with at least 50% pain relief with active and placebo treatment.© 2010 International Association for the Study of Pain”

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Conclusion

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“Pharmacological treatment still represents the main option for treating chronic neuropathic pain. Our understanding of neuropathic pain-generating mechanisms has grown considerably within the last few decades, but unfortunately this research has not been matched by a similar improvement in treatment efficacy. We are still limited in our efforts in managing neuropathic pain by relying on treating the symptoms of pain rather than identifying the underlying disease mechanisms causing the pain. Although 69 new randomized controlled trials have been published in the past 5years compared with 105 published trials published in the preceding 39years, only a marginal improvement in the treatment of the patients with neuropathic pain has been achieved.”

© 2010 International Association for the Study of Pain

The study is part of the European project, funded by the Innovative Medicines Initiative Joint Undertaking

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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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Posted in Anti-iinflammatory, Antidepressants, Chronic Pain, Neuropathy, Opioids, Pain Management, medicine, Research, Uncategorized. Leave a Comment »

Ketamine Intranasal for Rapid Relief of Pain and Depression

01/25/2012 — Nancy Sajben MD

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Poorly managed pain can evolve into chronic disease of the nervous system

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Ketamine is an important analgesic, more important than opioids. It can dramatically reduce pain, and rapidly relieve depression and PTSD.  Please read my earlier posts here and here. And the NPR report here just after I posted this (skip to their last section). Yes, it is FDA approved and legal. One woman said:

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 ’It was almost immediate, the sense of calmness and relaxation.

‘No more fogginess. No more heaviness. I feel like I’m a clean slate right now. I want to go home and see friends or, you know, go to the grocery store and cook the family dinner.’

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NPR again reports ketamine’s rapid relief of depression. A 28 year old man whose refractory depression began at age 15, after ketamine, says:

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‘I Wanted To Live Life’

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Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.”Monday afternoon I felt like a completely different person,” he says. “I woke up Tuesday morning and I said, ‘Wow, there’s stuff I want to do today.’ And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life.”.
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Since then, they treated him with Riluzole that is FDA approved for ALS and has one of the dirtiest side effect profiles I have ever seen in medicine with serious organ toxicity. Ketamine rarely causes mild transient side effects, usually none. It appears the concern is how ketamine is used on the street with potential for abuse. I do not see ketamine abuse in my patients, some of whom are on opioids for pain or Valium family medicines from their psychiatrist. All of those have a greater potential for abuse, also not occurring in my patients. Pain and/or depression can lead to suicide.
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About 18 months ago, researchers at Yale found a possible explanation for ketamine’s effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.
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Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

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It would be of interest to see a case report of the bladder problems they mention. Is this in a single drug addict who used many unknown medications on the street? Several physicians have infused IV ketamine for persons with pain for many years, in far higher doses than I prescribe, with no report of any but transient minor symptoms.

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David Barsook’s 2009 review, reference below, describes changes that cause memory loss and brain atrophy with chronic pain, in particular, Complex Regional Pain Syndrome (CRPS), and they also occur with chronic depression:

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With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death.

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Brain atrophy and memory loss has also been shown in chronic low back pain as well as in chronic depression.

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Barriers to management of chronic pain are many:

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Although opioids are effective for acute pain, effective treatment of chronic pain is often daunting, particularly neuropathic pain.

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Opioids have been shown to create pain causing imbalance in the glial cytokines that favor pain rather than relief of pain. Opioids carry the risk of opioid-induced hyperalgesia which is a severe pain sensitivity. They affect the brain and endocrine system. Opioids may fail to offer significant relief, fail to improve function, and risk misuse, abuse, diversion and death. Their costs are astronomic, insurance coverage is increasingly limited, the potential for complications may be life threatening in a hectic medical setting, side effects can be lethal, lack of physician training in use of opioids and alternatives to pain control lead to increasing deaths, addiction and diversion. It has become a national emergency and a trillion dollar war on drugs.

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Complications can be greatly reduced through use of a scrupulous history and physical examination, but reimbursement is directly proportional to the shortest time spent with a patient. Will that help assessment and care?

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Individuals may have dramatically different responses to opioid therapy; some may not tolerate any, and relief must be balanced with side effects that increase as the dose increases. Patient status may change and require IV, rectal or tube delivery instead of oral formulas; drug-drug interactions may require rapid changes, and disease of kidney, liver or brain may require modifications or stopping altogether. They may increase risk of falls and cause central sleep apnea with drop in oxygen because the brain fails to give a signal to breathe.

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Chronic pain can lead to loss of sleep, hopelessness, depression, anger and other mood disorders such as panic, anxiety, hypochondriasis and post traumatic stress disorder [PTSD]. Treatment of mood disorders are shown to profoundly reduce pain perception and/or ability to cope with pain.

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Ketamine is anti-inflammatory and can reduce the need for opioid use, thus reducing the pain and side effects caused by opioids.

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Nasal ketamine is more effective than oral ketamine for pain relief; oral dosing has no effect on depression.

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Nasal delivery of ketamine is now possible due to advances in metered nasal sprayers that deliver a precise dose. No needle is required, no IV access, no travel to a specialist needed.

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You can carry pain relief with you and use it as directed when it is needed.

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Ketamine is an NMDA antagonist: it antagonizes the NMDA receptor which plays a profound role in pain systems and centralization of pain.

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Ketamine is neuroprotective and it can help other disease states as noted by Barsook, 2009:

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Besides improvement in pain, “there may be lessons from other diseases that affect the brain; it is noteworthy that acute ketamine doses seem to reverse depression and ketamine decreased prevalence of post-traumatic stress disorder (PTSD) in soldiers receiving ketamine during their surgery for treatment of their burns. In addition ketamine attenuates post-operative cognitive dysfunction following cardiac surgery that has been known to produce significant changes in cognition. [emphasis mine] The data suggest that the drug can alter or prevent other conditions based on its NMDAR activity where other drugs NMDA receptor antagonists are perhaps not as effective in these or pain conditions. Lastly, NMDA antagonists have been used in degenerative disease (and pain may be considered a degenerative disease as defined by loss of gray matter volume, see above) with mixed effects perhaps relating to how they act on specific NMDA subtypes. Taken together, ketamine may act not only on sensory systems affecting pain intensity, but also on a constellation of brain regions that are involved in the pain phentype. [sic, phenotype]“

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Side Effects

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Ketamine is more frequently used in babies and children than in adults because high doses of ketamine can induce hallucinations in the adult. Importantly, it is used in high dose in adults for treatment of Complex Regional Pain Syndrome.

Low doses, cause little or no side effects in adults. If present, they are transient and often resolve in 20 minutes. Patient who respond to ketamine report good acceptance as they find the relief of pain and/or depression far outweighs any short term minimal discomfort.

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Pain care reform is urgently needed.

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Research funding for pain is less than half of one percent of the NIH budget. More research is needed, but research on low dose ketamine for treatment of pain and depression has gone on for twenty years.

The public health crisis of untreated pain, which often results in disability, parallels the country’s struggle to halt the cost of health care. The longer a person remains with untreated pain, the less likely they are to return to work or to be employable.

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Conclusion

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Pain control requires urgent attention. It is past time to put into practice the use of this valuable medication so people can get on with life instead of being mired in chronic pain that for many risks suicide and ensures continuing decades of disability. Academic studies are usually limited by defining a predetermined dose rather than clinically titrating to effect. Thus no surprise, they find no effect as every patient will have no response until they reach their dose. And that dose, in my experience, falls into a bell shaped curve. One size does not fit all. Some respond at very low dose, others require much more, and the majority fall between.

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In my experience prescribing ketamine for ten years, only a rare person has problems. Almost all find it has returned function or significantly relieved pain. Some have been able to entirely eliminate opioids that did nothing for their pain for decades, though they dutifully returned to the MD every month to chronicle that pain. Pain continued to be rated ten on a scale of ten; patient always compliant despite side effects of constipation and often depression. My patients find the benefits of nasal ketamine far outweigh the relief of oral ketamine and at much lower doses with fewer side effects.

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Further, while the pain relief may be short lived, some find it gets better with repeat dosing, and relief of depression may last one to two weeks with a single dose.

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References

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http://www.wjgnet.com/1007-9327/10/1028.asp  Ketamine suppresses intestinal NF-kappa B activation and proinflammatory cytokine in endotoxic rats.

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CONCLUSION: Ketamine can suppress endotoxin-induced production of proinflammatory cytokines such as TNF-a and IL-6 production in the intestine. This suppressive effect may act through inhibiting NF-kappa B.

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http://informahealthcare.com/doi/abs/10.1080/J354v16n03_03  Ketamine as an Analgesic Parenteral, Oral, Rectal, Subcutaneous, Transdermal and Intranasal Administration

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Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain.
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http://www.ncbi.nlm.nih.gov/pubmed/15109503  Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study  Daniel Carr, et al, 2004
Crossover, 20 patients. Ketamine reduced breakthrough pain within 10min of dosing, lasting up to 60min
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http://www.ncbi.nlm.nih.gov/pubmed/15288418  Safety and efficacy of intranasal ketamine in a mixed population with chronic pain
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The intranasal route for ketamine administration has been applied only for pain of dressing changes in a single case study (Kulbe, 1998). In this patient, oxycodone and acetaminophen were ineffective to control pain during burn dressing changes in a 96-year-old woman cared for at home. She tolerated the burn dressing changes after three intranasal sprays of 0.1 ml each, in rapid succession, each containing 5 mg ketamine (15 mg total) (Kulbe, 1998).
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http://www.acutepainjournal.com/article/S1366-0071%2807%2900167-2/abstract  Safety and efficacy of intranasal ketamine for acute postoperative pain
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Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50 mg, over a 3 h period. Rapid onset of analgesia was reported (<10 min), and meaningful pain relief was achieved within 15 min of the 50 mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics.
The safety profile following treatment with ketamine was comparable to that seen with placebo.
Although patients did report side effects of fatigue, dizziness and feelings of unreality more often following treatment with ketamine than following treatment with placebo, no patient reported hallucinations and the side effects were generally reported to be of mild or moderate severity, and transient. No serious adverse events were reported and the incidences of associated adverse events were comparable for ketamine and placebo. Although study medication was administered intranasally, nasal signs and symptoms were few and inconsequential. A distinctive taste, however, was reported more often following treatment with ketamine than following treatment with placebo.In conclusion this randomized, placebo-controlled, double-blind study, in 20 patients, has demonstrated that intranasal ketamine is safe and effective for BTP [breakthrough pain]. Our findings augment an early but promising literature documenting the effectiveness of nasal administration of a variety of opioids for pain management in adults (Dale et al., 2002) .
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~http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/  Ketamine and chronic pain – Going the distance, David Barsook, 2009

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This important paper covers essential points not mentioned by many, thus quoted at length below:

“Ketamine, brain function and therapeutic effect – neuroprotective or neurotoxic

With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations ; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death. Here lies the conundrum the use of an agent that potentially deleteriously affect neurons that may already be compromised but may also have neuroprotective properties by mechanisms that include reducing phosphorylation of glutamate receptors resulting in decreased glutamatergic synaptic transmission and reduced potential excitotoxicity . Alternatively, ketamine may affect glia regulation of glutamate and inhibit glutamate release within glia. However, by whatever mechanism ketamine acts on CRPS pain, there does seem to be a dose/duration effect in that longer doses at levels tolerated by patients seem to prove more effective in terms of the duration of effects.

So what could be happening in the brain and what is required to alter brain systems and reverse the symptomatic state? Ketamine may diminish glutamate transmission and “resets” brain circuits, but it seems that a minimal dose and/or duration of treatment is required. Alternatively, ketamine may produce neurotoxicity and damage or produce a chemical lesion of affected neurons. These two issues are important to be understood in future trials. Reports from patients who have had anesthetic doses have included prolonged pain relief for many months. While the authors did not address issues such as the effect of dosing duration or repetitive dosing at say 6weeks, they did show a level of efficacy based on NNT that equals or betters most drug trials for this condition.”

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“Conclusions

As a community we have a major opportunity to define the efficacy and use of a drug that may offer more to CRPS (and perhaps other) patients than is currently available. This is clearly an opportunity that needs urgent attention and a number of questions remain to be answered. For example, is ketamine more effective in early stage disease? How does ketamine provide long-term effects? Further controlled trials evaluating dose, duration, anesthetic vs. non-anesthetic dosing are needed. Few of us really understand what it is like to suffer from a chronic pain condition such as CRPS. Ketamine therapy may be a way forward that can be brought into our clinical practice through further controlled studies that will allow for appropriate standards for use in patients.”

 

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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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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!
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Posted in Anti-iinflammatory, Antidepressants, Anxiety, Back Pain, Chronic Pain, Complex Regional Pain Syndrome, CRPS, Depression, Failed back surgery, Fibromyalgia, Glia, Hyperalgesia, Immune Cells, Immune System, intractable pain, Ketamine, Medications, Memory Loss, Neuroprotective, Opioids, Pain Management, medicine, PTSD, Radiculopathy, RSD, Toxicity. Tags: , , , , , . 10 Comments »

Opioids Create Pain via Molecular and Genetic Changes

06/16/2009 — Nancy Sajben MD

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Chronic use of opioid pain medication

causes molecular and genetic changes that result in pain

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A brief update

American Pain Society May 2009 Symposia: Anti-analgesic Effects of Mu-opioids: Molecular and Genetic Mechanisms

The clinical benefits of opioid analgesics have not been fully realized due to substantial side effects, which include tolerance, dependence and opioid-induced hyperalgesia. Although the precise molecular mechanism of these phenomenon is not understood yet, it is generally thought to result from cellular excitatory effects of mu-opioids which contrast the major inhibitory effects.

Mark Hutchinson, PhD, discussed the new discovery that every clinically relevant class of opioid analgesics non-stereoselectively activates glial cells through TRL4 receptor. Activation of this receptor, primarily expressed by microglia, leads to the release of proinflammatory mediators that counter-regulate acute opioid analgesia.

How can opioid-induced glial activation oppose & augment different aspects of opioid action?

Opioid analgesia is opposed by opioid-induced spinal glial activation since increased neuronal excitability leads to elevated nociception. Increased brain opioid-induced glial activation also leads to increased neuronal excitability & within reward & dependence centers this is believed to increase opioid reward & dependence. Therefore analgesia is decreased & reward/dependence is increased.

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Counteracting hyperalgesia with naltrexone and dextromethorphan

In summary, Dr. Hutchinson describes the TRL4 receptor where opioids act to induce activation of microglia, releasing proinflammatory mediators that counteract analgesia and produce more pain.

Naltrexone, a mu opioid antagonist, has profound anti-inflammatory effects centrally on the microglia to produce analgesia.  This mechanism of action of low dose naltrexone is discussed here.

Dextromethorphan acts centrally on microglia by the same mechanism, producing analgesia.  Both naltrexone and dextromethorphan are classified as morphinans, morphine-like.·

More is less:  increasing the dose causes pain.

A steep road to climb, much less to understand.

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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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Posted in Hyperalgesia, Medications, Opioids, Research. Tags: , . Leave a Comment »
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