RNcrps2 -

There is a variation/combination of ketamine (or other NDMA-receptor antagonists and some other drugs as well) along with the pump that should be considered as well. But some background is in order. For a long time, we've known obout "opioid-induced hyperalgesia," defined in open-source (and freely useable, thank you) Wikipedia as follows:

Opioid-induced hyperalgesia[1] or opioid-induced abnormal pain sensitivity[2] is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.[3]

Although tolerance and opioid-induced hyperalgesia both result in a similar need for dose escalation, they are nevertheless caused by two distinct mechanisms.[4] The similar net effect makes the two phenomena difficult to distinguish in a clinical setting. Under chronic opioid treatment, a particular individual's requirement for dose escalation may be due to tolerance (desensitization of antinociceptive mechanisms), opioid-induced hyperalgesia (sensitization of pronociceptive mechanisms), or a combination of both. Identifying the development of hyperalgesia is of great clinical importance since patients receiving opioids to relieve pain may paradoxically experience more pain as a result of treatment. Whereas increasing the dose of opioid can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hyperalgesia may worsen the patient's condition by increasing sensitivity to pain while escalating physical dependence.

Notes
1. Angst, MS & Clark, DJ: Opioid-induced hyperalgesia: A qualitative systematic review. Anesthesiology 2006; 104:570–87
2. Mao J: Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy. Pain 2002; 100:213–7
3. Celerier E, Laulin J-P, Corcuff J-B, Le Moal M, Simonnet G: Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: A sensitization process. J Neurosci 2001; 21:4074–80
4. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain. 2008 Jul-Aug;24(6):479-96. PMID 18574358

Opioid-induced hyperalgesia, Wikipedia, the free encyclopedia, http://en.wikipedia.org/wiki/Opioid-...d_hyperalgesia (last accessed February 10, 2010)

And in that regard, we have numerous peer-reviewed articles, such as the following by Sanford M. Silverman, M.D., Opioid Induced Hyperalgesia: Clinical Implications for the Pain Practitioner, Pain Physician 2009; 12:679-684 FREE FULL TEXT AT http://www.painphysicianjournal.com/...12;679-684.pdf:

Abstract
Opioids have been and continue to be used for the treatment of chronic pain. Evidence supports the notion that opioids can be safely administered in patients with chronic pain without the development of addiction or chemical dependency. However, over the past several years, concerns have arisen with respect to administration of opioids for the treatment of chronic pain, particularly non-cancer pain. Many of these involve legal issues with respect to diversion and prescription opioid abuse. Amongst these, opioid induced hyperalgesia (OIH) is becoming more prevalent as the population receiving opioids for chronic pain increases. OIH is a recognized complication of opioid therapy. It is a pro-nocioceptive process which is related to, but different from, tolerance. This focused review will elaborate on the neurobiological mechanisms of OIH as well as summarize the pre-clinical and clinical studies supporting the existence of OIH. In particular, the role of the excitatory neurotransmitter, N-methyl-D-aspartate appears to play a central, but not the only, role in OIH. Other mechanisms of OIH include the role of spinal dynorphins and descending facilitation from the rostral ventromedial medulla. The links between pain, tolerance, and OIH will be discussed with respect to their common neurobiology. Practical considerations for diagnosis and treatment for OIH will be discussed. It is crucial for the pain specialist to differentiate amongst clinically worsening pain, tolerance, and OIH since the treatment of these conditions differ. Tolerance is a necessary condition for OIH but the converse is not necessarily true. Office-based detoxification, reduction of opioid dose, opioid rotation, and the use of specific NMDA receptor antagonists are all viable treatment options for OIH. The role of sublingual buprenorphine appears to be an attractive, simple option for the treatment of OIH and is particularly advantageous for a busy interventional pain practice.

PMID: 19461836 [PubMed - indexed for MEDLINE]

Thus, much can be gained by just tinkering with the medications, including opioid rotation and using the opioid with drugs that strengthen the opioid analgesic effects (a “potentiater”) to the point that you are actually taking lesser amounts of the narcotic – with all of its side effects – or by otherwise using an opioid or “partial opioid” that also interferes with pain signaling between the brain and the spinal column. From what I understand, the principal drugs that are either “full” or “partial” opioids, while at the same time interfering with pain path signaling are Methadone and Buprenorphine (Subutex).

And interestingly, Buprenorphine has been combined with trace amounts (millionths of a gram) of a powerful anti-opioid drug developed to treat overdoses, Nalaxone HCL (Narcan), which can act as a powerful potentiater. For a good recent article in the area - and one of hundreds - check out, Abul-Husn NS, et al., Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists, Br J Pharmacol. 2007 Jul;151(6):877-87, FREE FULL TEXT AT http://www.ncbi.nlm.nih.gov/pmc/arti...3/?tool=pubmed

Abstract
BACKGROUND AND PURPOSE:
Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of micro and delta receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception.

EXPERIMENTAL APPROACH: Effects of intrathecal administration of mu-receptor antagonists, CTOP (0.01 ng) or CTAP (0.001 ng), or a delta-receptor antagonist, naltrindole (0.01 ng), on spinal morphine analgesia and tolerance were evaluated using the tail-flick and paw-pressure tests in rats.

KEY RESULTS: Both micro and delta antagonists augmented analgesia produced by a sub-maximal (5 microg) or maximal (15 microg) dose of morphine. Administration of the antagonists with morphine (15 microg) for 5 days inhibited the progressive decline of analgesia and prevented the loss of morphine potency. In animals exhibiting tolerance to morphine, administration of the antagonists with morphine produced a recovery of the analgesic response and restored morphine potency.

CONCLUSIONS AND IMPLICATIONS: Combining ultralow doses of micro- or delta-receptor antagonists with spinal morphine augmented the acute analgesic effects, inhibited the induction of chronic tolerance and reversed established tolerance. The remarkably similar effects of micro- and delta-opioid receptor antagonists on morphine analgesia and tolerance are interpreted in terms of blockade of the latent excitatory effects of the agonist that limit expression of its full activity.

http://www.ncbi.nlm.nih.gov/pubmed/17502848

The one drug on the market that actually combines the two is called Suboxone and is marketed to treat drug dependence. I’m not sure if the proportions of the two drugs in Suboxone are perfect for its use as a potentiated analgesic, but if you do a term-search for “Suboxone” in this forum, you will find some people who swear by it.

But the problem is that Suboxone (for FDA approved prescribing information, see http://www.suboxone.com/pdfs/SuboxonePI.pdf ) is that it's titrated to assis in the weaning off of narcotic dependency, not necessarily for maximum analgesis effect, which could in theory vary slightly from person to person.

The pump could moot the questiion, putting a good pain specialist in the driver's seat, lawfully administering a combination of FDA approved drugs in a pain pump, and notwithstanding which recipe is chosen (full/partial opiod plus either a potentiated such as micro-doses of nalaxone or an NDMA-receptor antagonist, ranging conceivably from low, low dose ketamine to the over-the-counter cough suppressant dextromethorphan) all in what may be the very near future.

And the best part is, not only is the "augmented" opioid a much better analgesic, but the patient gets far less of it, ergo fewer complications. Potentially a whole new world, right around the corner. (Seroiusly, if you search "Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists" on PubMed, you'll pull up the abstract I've quoted above, then go to the right hand side of the page a click "See all" under related articles, and you will get 2.603 hits, of which 548 will be freely avaiable in full text!)

For those whose pain is at the point where it boils down to the choice between a ketamine coma or a dilaudid pump, it's worth a conversation with your pain dr. in any event.

Mike