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Treatment of CRPS pain acc to protocol including ketamine (&DMSO) creams

In our clinic we developed a new treatment protocol for pains in CRPS, Sudeck's dystrophic pains. We combine various treatments, all with a low propensity for side-effects. Basically our treatment protocol consists of:

1. Topical analgesic creams:

a. start with ketamine 10% racemic cream and on top of it (if necessary) DMSO 50% cream. 

b. or switch to amitriptyline 10% cream ( with/without DMSP 50%)

c. switch to een PEA-houdend product cream on top of either one of the creams before (consisting of the immune-modulator adelmidrol and capsaicine low concentration)

Creams in addition to:

2. een PEA-houdend product (palmitoylethanolamide) 600 mg twice daily.

Start with 20-30 days on een PEA-houdend product powder sublingually (melt in saliva under tongue, not to swallow, but to resorp in the mounth, and after treat with een PEA-houdend product 600 mg tablets twice daily. (order by www.ergomax.nl)

Topical creams in CRPS: background 

Chronic severe pain in Sudeck or CRPS we treat with a combination of various topical creams, especially a 10% ketamine cream, in severe cases together with DMSO 50% cream. Topical analgesics have clearly advantages over systemically administered medications. This is especially true for racemic ketamine. The reduction or elimination of side-effects is one of the major advantages.

Many patients are totally unable to ingest ketamine, but as a cream the application of ketamine is no problem. We treated already 40 patients without any problems, and a Canadian academic group decribed another group of 60 patients. Topical analgesics differ from transdermal delivery methods in that prescribers use topical applications to deliver local, rather than systemic effects.

In our institute we have developed a variety of special-compounded creams to improve our patients’ experience with intractable pain due to Sudeck / CRPS. Ketamine 10% is one example.We also developed amitriptyline cream, baclofen cream and gabapentine creams. 

Our compounded ketamine 10% cream can be used for specific patients in e.g. the Netherlands, Germany and the UK if the physicians order a prescription document at infoneuropathie.nu.gif

Ketamine 10% cream for Sudeck (CRPS) pain

One of our compounded cream very useful for some Sudeck patients is a topical 10% ketamine cream. Its mechanism of action is most probably linked to peripheral N-methyl-D-aspartate (NMDA) receptors, important for the sensation of severe pain.


 

Ketamine blocks NMDA and 5HT receptors, Na+ and Ca+ channels, and the edema response associated with inflammation.

In addition to that, ketamine binds to many sites in the central and peripheral nervous systems including nicotinic, muscarinic, opioid, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), kainate, and gamma-aminobutyric acid A (GABA-A) receptors.

Topical ketamine applications have documented success in neuropathic pain patients, in terms of providing some direct analgesia and inhibiting sympathetically maintained pain. [1]

The most important use of our compounded ketamine cream is the reduction of hyperalgesia (an exaggerated pain sensation to a painful stimulus), and the reduction of allodynia (a painful sensation elicited by a nonpainful stimulus). [ref=9178844]

In literature one can find support for topical ketamine applications for pain management in a variety of pain states: post-surgical neuropathic pain, complex regional pain syndrome as in Sudeck, hernia or lumbar radiculopathic pain, proctodynia pain, diabetic neuropathic pain, oral pains and post-herpetic neuralgia. [2] [3] [4]  [5] [6] [7] [8] [9] [10]

Evidence points out that ketamine cream acts only locally. After applying a 10% ketamine cream compound, no ketamine could be detected in the bloodstream in a trial in 20 patients, and ketamine applied to healthy limbs produced no effect in painful limbs.  [11]

This sorts of compounded topical ketamine formulations have no documented side effects and its efficacy has also been described in CRPS. [12]

Availability of ketamine 10% cream for physicians

Our compounded cream can be used for specific patients in e.g. the Netherlands, Germany and the UK if the physicians order a prescription document at *protected email*

Summary of Evidence on Ketamine Analgesia

Level 1 (Evidence obtained from a systematic review (or meta-analysis) of 
all the relevant RCTs):

  1. Low-dose perioperative ketamine is opioid sparing, reduces nausea and
  2. vomiting, and has minimal side effects.
  3. Ketamine added to opioid PCA provides no additional analgesic benefit.
  4. Ketamine is most effective as a continuous low-dose infusion for acute pain
  5. management.
  6. Ketamine has “preventive” but not “preemptive” analgesic effects.
  7. Ketamine is a safe and effective sedative/analgesic for painful procedures,
  8. particularly in children.

Level II (Evidence obtained from at least one properly designed RCT)

  1. Ketamine is most effective as an “antihyperalgesic,” “antiallodynic,” or
  2. “tolerance-protective” treatment.
  3. Ketamine is effective as a “rescue analgesic” for acute pain unresponsive to
  4. opioids.
  5. Ketamine reduces acute wound hyperalgesia and allodynia.
  6. Ketamine may reduce the incidence of chronic postsurgical pain following
  7. laparotomy, thoracotomy, and mastectomy.
  8. Ketamine reduces lower-limb ischemic rest pain, peripheral neuropathic pain,
  9. and spinal cord injury pain.
  10. Ketamine improves fibromyalgia symptoms, including tender point count and
  11. aerobic endurance.
  12. Intranasal ketamine reduces breakthrough pain of cancer-related and
  13. noncancer origin.
  14. Ketamine reduces migraine severity in both acute and prophylactic therapy.
  15. Ketamine does not improve analgesia when used alone or in combination with
  16. local anesthetic for peripheral nerve blocks, intra-articular injection, or wound
  17. infiltration.

Level III (Evidence obtained from nonrandomized controlled trials)

  1. Ketamine may be effective for refractory cancer pain in terminal stage disease.
  2. Ketamine may reduce severe chronic phantom limb pain.

Level IV (Evidence obtained from case series)

  1. Ketamine improves analgesia in opioid-tolerant patients.
  2. Intranasal ketamine may relieve migraine aura.
  3. Ketamine may be effective in visceral pain based on human experimental
  4. models and limited case reports.
  5. At least 50% of patients fail to respond to oral ketamine and experience side
  6. effects in the treatment of chronic neuropathic pain.
  7. Long-term ketamine use may be associated with impairment of memory,
  8. attention, and judgment.  

Additional References on topical ketamine cream in CRPS

Keppel Hesselink, JM and DJ Kopsky, Letter to editor, current therapeutic research 2010, 71, 6: 416-417

Trist D. Excitatory amino acid agonists and antagonists: pharmacology and therapeutic applications. Pharm Acta Helv 2000; 74: 221-9.
Sang C. NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage. 2000; 19: S21-S25.

Gammaitoni A, Gallagher R, Welz-Bosna M. Topical ketamine gel: possible role in treating neuropathic pain. Pain Med. 2000; 1(1): 97-100.

Crowley K, Flores J, Hughes C, et al. Clinical application of ketamine ointment in the treatment of sympathetically maintained pain. Int J Pharmaceut Compound. 1998; 2: 122-127.

September 2011, prof. dr. Jan M. Keppel Hesselink, MD, PhD and David J Kopsky, MD, revision november 2011, JMKH  

Referentie

[1] Pöyhiä R, Vainio A. | Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia. | Clin J Pain. | 2006 Jan;22(1):32-6.

[2] Lehman JS, Sciallis GF. | Effective use of topical amitriptyline hydrochloride 2.5% and ketamine hydrochloride 0.5% for analgesia in refractory proctodynia. | J Drugs Dermatol. | 2008 Sep;7(9):887-9.

[3] Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. | Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study. | J Pain. | 2005 Oct;6(10):644-9.

[4] Lynch ME, Clark AJ, Sawynok J. | A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. | Clin J Pain. | 2003 Sep-Oct;19(5):323-8.

[5] Perutz MF. | Mechanisms regulating the reactions of human hemoglobin with oxygen and carbon monoxide. | Annu Rev Physiol. | 1990;52:1-25.

[6] Prommer EE. | Topical analgesic combinations for bortezomib neuropathy. | J Pain Symptom Manage. | 2009 Mar;37(3):e3-5. Epub 2009 Jan 25.

[7] Canbay O, Celebi N, Uzun S, Sahin A, Celiker V, Aypar U. | Topical ketamine and morphine for post-tonsillectomy pain. | Eur J Anaesthesiol. | 2008 Apr;25(4):287-92. Epub 2008 Jan 11.

[8] Gammaitoni A, Gallagher RM, Welz-Bosna M. | Topical ketamine gel: possible role in treating neuropathic pain. | Pain Med. | 2000 Mar;1(1):97-100.

[9] Slatkin NE, Rhiner M. | Topical ketamine in the treatment of mucositis pain. | Pain Med. | 2003 Sep;4(3):298-303.

[10] Quan D, Wellish M, Gilden DH. | Topical ketamine treatment of postherpetic neuralgia. | Neurology. | 2003 Apr 22;60(8):1391-2.

[11] Finch PM, Knudsen L, Drummond PD. | Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine. | Pain. | 2009 Nov;146(1-2):18-25. Epub 2009 Aug 22.

[12] Ushida T, Tani T, Kanbara T, Zinchuk VS, Kawasaki M, Yamamoto H. | Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1. | Reg Anesth Pain Med. | 2002 Sep-Oct;27(5):524-8.