TXguidelines_pharmacotherapy.

pdf

CALCITONIN
Interestingly enough, calcitonin is one of the best-studied drugs in the treatment of CRPS. 96-99 A
polypeptide
hormone, calcitonin provides some analgesic effects and it regulates both bone metabolism and blood
calcium levels.98
A meta-analysis100 of a limited number of controlled studies (level 1 evidence) demonstrates the value
of intranasal
doses of 100-300 U per day for the management of CRPS.98, 100, 101 Two other clinical trials 96, 98 of
calcitonin in
CRPS, however, which were both identified as high-quality studies (level 2 evidence) in a systematic
review, reported
conflicting results.23 One study reported significant improvement in pain intensity after administration
of 100 IU
calcitonin thrice daily for 3 weeks.98 The other study reported no improvement after administration of
200 IU
calcitonin twice daily for 4 weeks.96

http://www.ncbi.nlm.nih.gov/sites/entrez?
cmd=Retrieve&db=PubMed&list_uids=11844639&dopt=Abstract

J Pain Symptom Manage. 2002 Feb;23(2):165-70. Related Articles, Links

Low dose ketamine as an analgesic adjuvant in difficult pain syndromes: a strategy for
conversion from parenteral to oral ketamine.

Fitzgibbon EJ, Hall P, Schroder C, Seely J, Viola R.

University of Ottawa Institute of Palliative Care, Ottawa, Ontario, Canada.

Ketamine is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist with

analgesic and dissociative anesthetic properties. Low dose or sub-anesthetic doses of
ketamine have been used effectively as either a primary analgesic or analgesic adjuvant
in a variety of pain syndromes. In this paper, three patients with difficult to treat,
predominantly neuropathic pain syndromes will be described. Their pain syndromes were
initially managed successfully with the addition of low dose parenteral ketamine as an
analgesic adjuvant. The strategy of concurrently starting ketamine at a low dose, i.e., 40-
60 mg over 24 hours, with a benzodiazepine proved effective in preventing
psychotomimetic side effects. An unavoidable shortage of ketamine prompted a literature
search, which suggested that the equianalgesic dose of oral ketamine could be lower than
the parenteral dose. Subsequently the patients were converted to oral ketamine at doses
30 to 40% of the previous parenteral dose. Their pain syndromes remained controlled on
the lower dose of oral ketamine with remarkably few side effects. The implications of
this warrant further discussion and study.

http://www.freepatentsonline.com/20050148673.html

Prolonged administration of ketamine NMDA antagonist and safener drug to alter neuropathic pain condition - Patent 20050148673.html

Prolonged administration of NMDA antagonist and safener drug to alter neuropathic pain
condition
Document Type and Number:
United States Patent 20050148673
Kind Code:
A1
Link to this page:
http://www.freepatentsonline.com/20050148673.html
Abstract:
A drug that inhibits NMDA receptors (such as ketamine, a surgical anesthetic) is
continuously administered to patients suffering from neuropathic pain. Unless the NMDA
antagonist drug has inherent safening activity, this treatment requires a "safener" drug to
prevent the neurotoxic side effects of NMDA antagonists. One class of safener drugs that
increase the efficacy of the treatment include alpha-2 adrenergic agonists, such as
clonidine. The treatment lasts for several days and nights, continuously. A maximum
tolerated dosage is titered for each patient, such as by observing slurring of speech, and
the patient does not lose consciousness except during normal sleep. Magnesium and/or
drugs that inhibit ketamine-degrading enzymes can also be used. Patients who suffered
for years from chronic intractable pain emerged from this treatment with apparently
permanent relief, or with lasting reductions in their levels of
pain.

0000000000000000000000000000000000000000000000000000000000000000000000

ketamine cancer.html

http://www.meb.uni-bonn.de/Cancernet/304470.html
http://www.meb.uni-bonn.de/Cancernet/304470.html

N-methyl-D-aspartate (NMDA) Receptor Antagonists

There is increasing interest in the evidence for the importance of NMDA receptors, and
the possibility that NMDA antagonists may have a role in refractory cancer pain
management.[129,147] Ketamine in subanesthetic doses has been used in this setting. Co-
administration of a neuroleptic or benzodiazepine is given to limit the emergence of side
effects. Ketamine is generally given subcutaneously at a low starting dose, such as 0.1
mg per kg of body weight per hour with a gradual escalation. It has been suggested that
oral ketamine may be a more potent analgesic and have a more favorable side effect
profile than parenteral ketamine.[144] A recent novel approach suggested short duration
therapy of a continuous subcutaneous infusion of ketamine over 3 to 5 days. The initial
dose is 100 mg per day, and if pain control is inadequate, the dose is escalated to 300 mg
per day and then to a maximum dose of 500 mg per day. Treatment is continued for three
days at either the lowest effective dose or 500 mg per day and then discontinued.[147]

---------------------------------------------
Desipramine has the fewest anticholinergic and
sedative side effects of all the TCAs. Patients taking amitriptyline,
the TCA with the most side effects, often tolerated therapy far
better than when switched to desipramine. If concern about side

9999999999999999999999999999999999999999

http://gateway.tx.ovid.com/gw2/ovidweb.cgi?
&S=LHNBFPEDHODDNGMBNCILBECKKPPPAA00&FTS+Content=S.sh.2.14.15%7
c20%7c%2fbookdb%2f00139962%2f3rd_Edition%2f2%2fPG
%280%29&ReturnToBrowseBooks=Browse+Content%3dS.sh.2.14%7c0%7c20

book: Massuchusetts pain management

1. Tricyclic Antidepressants
Historically, the TCAs have been the mainstay of medical therapy for neuropathic pain.
They are well studied and widely prescribed. There is strong evidence of efficacy in
diabetic neuropathy and postherpetic neuralgia and they are effective for most
neuropathic pain symptoms. Despite this, patients only rarely obtain complete relief and
often are unable to tolerate the side effects of this class. Caution is needed in patients
with cardiovascular disease, closed-angle glaucoma, and dementia.
Older patients or those on complicated regimens should begin at the lowest dose.
Tolerability and degree of relief guide the process of weekly dose escalation in small
increments. It is important to proceed slowly in the early phase of titration as the
anticholinergic side effects (e.g., constipation, dry mouth, and confusion) may prompt
susceptible patients to discontinue medication prematurely. Most patients experience pain
relief in the range of 30 to 100 mg per day of desipramine or nortriptyline. If at the upper
end of this range, significant relief is not attained, other therapies should be tried.
Venlafaxine and duloxetine also inhibit serotonin and norepinephrine reuptake and may
have fewer side effects than the TCAs; however, evidence of efficacy is not as strong as
for TCAs.

Sympathetic neurolysis has been advocated in the past but is no longer recommended.
Chemical neurolysis lasts only 3 to 6 months, and patients may then suffer a recurrence,
or even worsening, of their original pain. There is also a risk of spread of the neurolytic
agent to the sensorimotor fibers in close proximity to the targeted nerves (e.g., phrenic
nerve, lumbar plexus). In addition, there is a high risk of deafferentation pain, which is
worse and harder to treat than the initial pain. More recently, percutaneous
radiofrequency lesioning of the sympathetic trunk and endoscopic sympathectomy have
been used in selected patients with clearly demonstrable SMP. Long-term evaluation of
these treatments has not yet been completed. However, current experience suggests there
may be a similar risk of deafferentation pain.

Rsd

Temperature/color change
Edema
Trophic skin, hair, nail growth abnormalities
Impaired motor function
Hyperpathia/allodynia
Sudomotor changes

CLINICAL Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication
Follow-up Miscellaneous Bibliography

History: The International Association for the Study of Pain (IASP) lists the diagnostic
criteria for CRPS I (RSDS) as follows:

The presence of an initiating noxious event or a cause of immobilization

Continuing pain, allodynia (perception of pain from a nonpainful stimulus), or
hyperalgesia disproportionate to the inciting event

Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor
activity in the area of pain

The diagnosis is excluded by the existence of any condition that would otherwise account
for the degree of pain and dysfunction.

According to the IASP, CRPS II (also known as causalgia) is diagnosed as follows:

The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not
necessarily limited to the distribution of the injured nerve

Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor
activity in the region of pain

The diagnosis is excluded by the existence of any condition that would otherwise account
for the degree of pain and dysfunction.

Note that the primary difference between type I and type II is the identification of a
definable nerve injury.

Older literature records cardinal and secondary signs. They are worth noting primarily
because they expand on the constellation of signs and symptoms the ED physician may
see in patients.
Cardinal signs include pain, edema, stiffness, and discoloration.
Pain that is intense and burning, out of proportion to the injury, and affects the entire
extremity occurs with RSDS.

Hyperpathia refers to pain that persists after the stimulus has been removed.

Allodynia refers to pain with light touch.

Movement frequently aggravates pain.

Patients describe exacerbations with cold. Many feel worse when a low-pressure weather
front is arriving. Airplane ascent and descent can be painful.
Edema is usually one of the earliest findings.
Stiffness may occur.
Discoloration may vary from intensely erythematous to cyanotic, pale, purple, or gray.
Lankford's secondary characteristics include the following:
Demineralization and osteoporosis are among the most classic (late) findings.
Sudomotor changes vary from hyperhidrosis to dryness.
Temperature difference between affected and unaffected extremities may be marked but
is usually measurable at some point in time.
Vasomotor instability most commonly is manifested as decreased capillary refill.
Erythema may be a sign of increased capillary refill and should be compared with refill in
unaffected extremity.
Skin may develop a glossy shiny appearance. In late stages, trophic changes may involve
a decrease in subcutaneous tissue.
In RSDS of the hand, nodules and thickening of the palmar fascia may develop.

0--------------------------------------------------
Departments of Orthopedic Surgery, Kochi Medical School, Nankoku, Kochi, Japan.
ushidat-koc@umin.ac.jp

OBJECTIVE: Ketamine hydrochloride (KET), an agent used for general anesthesia, has
local anesthetic effects and N-methyl-D-aspartate (NMDA) receptor antagonist action.
Because recent studies emphasized the role of peripherally distributed NMDA receptors
in processing the nociceptive information, we investigated whether peripheral application
of the ointment containing KET is able to attenuate the symptoms of local neuropathic
pain. CASE REPORTS: We applied ointment containing KET (0.25%-1.5%) to the
affected area on limbs in 5 patients with complex regional pain syndrome type I (CRPS I)
and in 2 patients with type II (CRPS II). One to 2 weeks later, we observed improvement
of the report of pain intensity, measured by the visual analog scale, in 4 patients with
acute early dystrophic stage of CRPS I. Swelling of the affected limbs subsided as well.
No apparent changes were noticed in 1 patient with chronic atrophic stage of CRPS I and
in both patients with CRPS II. CONCLUSION: Topical application of KET appears to be
beneficial for the patients with acute early dystrophic stage of CRPS I because of either
its local anesthetic effect or NMDA receptor antagonist action. Patients with chronic
atrophic stage of CRPS I and CRPS II patients do not appear to respond to this treatment.

PMID: 12373705 [PubMed - indexed for MEDLINE]

Low-Dose Ketamine May Be Helpful for Chronic Regional Pain Syndrome

Laurie Barclay, MDInformation from Industry

An Effective Treatment Option for Migraine Prevention
Lives are interrupted and negatively impacted by migraines. Learn more about how
migraine prevention may make a difference.

Oct. 6, 2004 — Low-dose ketamine may be effective for the treatent of chronic regional
pain syndrome (CRPS), according to a retrospective review published in the October
issue of Pain Medicine.
"CRPS is a disorder that can be accompanied by severe pain that is often both chronic
and resistant to conventional therapy," write Graeme E. Correll, BE, MBBS, FANZCA,
from Mackay Base Hospital in Queensland, Australia, and colleagues. "It is possible that
a more successful approach to desensitization therapy using an NMDA antagonist such as
ketamine requires a more individualized stepwise tailoring of the dosage (i.e., infusion
rate) and duration of drug administration."

The authors reviewed the medical records of 33 inpatients with CRPS treated in
Queensland at least once with a continuous subanesthetic intravenous infusion of
ketamine. After the first treatment, 25 patients (76%) had complete pain relief, six
patients (18%) had partial relief, and two patients (6%) had no relief. Of the 33 patients,
54% remained pain-free for at least three months and 31% remained pain-free for at least
six months after the first course of therapy.

Because of relapse, 12 of these patients received a second course of ketamine, and two
patients received a third course. All 12 of these patients had complete relief of their
CRPS pain. After the second treatment, 58% of 12 patients experienced relief for at least
one year, and nearly one third remained pain-free for at least three years.

The most frequently observed adverse effect was a feeling of inebriation. Six patients had
hallucinations, and four patients had changes in liver enzymes that resolved when the
infusion was terminated. Less frequent adverse effects were lightheadedness, dizziness,
and nausea.

"This retrospective review suggests that limited subanesthetic inpatient infusions of

ketamine may offer a promising therapeutic option in the treatment of appropriately
selected patients with intractable CRPS," the authors write. "More study is needed to
further establish the safety and efficacy of this novel approach."

While awaiting further data, the authors recommend limiting the duration of a continuous
ketamine infusion treatment to a maximum of four to five days, limiting the maximum
infusion rate to about 25 to 50 mg per hour, and combining
ketamine with a suitable neuroprotective agent.

Pain Med. 2004;5(3):263-275

Reviewed by Gary D. Vogin, MD

Related Links
Conference Articles

The Use of Topical Analgesics in the Treatment of Neuropathic Pain: Mechanism of

Action, Clinical Efficacy, and Psychologic Correlates
Resource Centers
Advanced Approaches to Chronic Pain Management Resource Center
Pharmacologic Management of Pain Resource Center

Laurie Barclay, MD is a freelance reviewer and writer for Medscape.

Medscape Medical News 2004. © 2004 Medscape

Send press releases and comments to news@medscape.net.

• About Medscape • Privacy & Ethics • Terms of Use • WebMD Health• WebMD
Corporate • Help
All material on this website is protected by copyright, Copyright © 1994-2007 by
Medscape. This website also contains material copyrighted by 3rd parties. Medscape
requires Microsoft browsers in versions 6 or higher.

Rsd

Temperature/color change
Edema
Trophic skin, hair, nail growth abnormalities
Impaired motor function
Hyperpathia/allodynia
Sudomotor changes

CLINICAL Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication
Follow-up Miscellaneous Bibliography
History: The International Association for the Study of Pain (IASP) lists the diagnostic
criteria for CRPS I (RSDS) as follows:

The presence of an initiating noxious event or a cause of immobilization

Continuing pain, allodynia (perception of pain from a nonpainful stimulus), or

hyperalgesia disproportionate to the inciting event

Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor
activity in the area of pain

The diagnosis is excluded by the existence of any condition that would otherwise account
for the degree of pain and dysfunction.

According to the IASP, CRPS II (also known as causalgia) is diagnosed as follows:

The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not
necessarily limited to the distribution of the injured nerve

Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor
activity in the region of pain

The diagnosis is excluded by the existence of any condition that would otherwise account
for the degree of pain and dysfunction.

Note that the primary difference between type I and type II is the identification of a
definable nerve injury.

Older literature records cardinal and secondary signs. They are worth noting primarily
because they expand on the constellation of signs and symptoms the ED physician may
see in patients.
Cardinal signs include pain, edema, stiffness, and discoloration.
Pain that is intense and burning, out of proportion to the injury, and affects the entire
extremity occurs with RSDS.

Hyperpathia refers to pain that persists after the stimulus has been removed.

Allodynia refers to pain with light touch.

Movement frequently aggravates pain.

Patients describe exacerbations with cold. Many feel worse when a low-pressure weather
front is arriving. Airplane ascent and descent can be painful.
Edema is usually one of the earliest findings.
Stiffness may occur.
Discoloration may vary from intensely erythematous to cyanotic, pale, purple, or gray.
Lankford's secondary characteristics include the following:
Demineralization and osteoporosis are among the most classic (late) findings.
Sudomotor changes vary from hyperhidrosis to dryness.
Temperature difference between affected and unaffected extremities may be marked but
is usually measurable at some point in time.
Vasomotor instability most commonly is manifested as decreased capillary refill.
Erythema may be a sign of increased capillary refill and should be compared with refill in
unaffected extremity.
Skin may develop a glossy shiny appearance. In late stages, trophic changes may involve
a decrease in subcutaneous tissue.
In RSDS of the hand, nodules and thickening of the palmar fascia may develop.

0--------------------------------------------------
Departments of Orthopedic Surgery, Kochi Medical School, Nankoku, Kochi, Japan.
ushidat-koc@umin.ac.jp

OBJECTIVE: Ketamine hydrochloride (KET), an agent used for general anesthesia, has
local anesthetic effects and N-methyl-D-aspartate (NMDA) receptor antagonist action.
Because recent studies emphasized the role of peripherally distributed NMDA receptors
in processing the nociceptive information, we investigated whether peripheral application
of the ointment containing KET is able to attenuate the symptoms of local neuropathic
pain. CASE REPORTS: We applied ointment containing KET (0.25%-1.5%) to the
affected area on limbs in 5 patients with complex regional pain syndrome type I (CRPS I)
and in 2 patients with type II (CRPS II). One to 2 weeks later, we observed improvement
of the report of pain intensity, measured by the visual analog scale, in 4 patients with
acute early dystrophic stage of CRPS I. Swelling of the affected limbs subsided as well.
No apparent changes were noticed in 1 patient with chronic atrophic stage of CRPS I and
in both patients with CRPS II. CONCLUSION: Topical application of KET appears to be
beneficial for the patients with acute early dystrophic stage of CRPS I because of either
its local anesthetic effect or NMDA receptor antagonist action. Patients with chronic
atrophic stage of CRPS I and CRPS II patients do not appear to respond to this treatment.

PMID: 12373705 [PubMed - indexed for MEDLINE]

Low-Dose Ketamine May Be Helpful for Chronic Regional Pain Syndrome

Laurie Barclay, MDInformation from Industry

An Effective Treatment Option for Migraine Prevention
Lives are interrupted and negatively impacted by migraines. Learn more about how
migraine prevention may make a difference.
Oct. 6, 2004 — Low-dose ketamine may be effective for the treatent of chronic regional
pain syndrome (CRPS), according to a retrospective review published in the October
issue of Pain Medicine.

"CRPS is a disorder that can be accompanied by severe pain that is often both chronic
and resistant to conventional therapy," write Graeme E. Correll, BE, MBBS, FANZCA,
from Mackay Base Hospital in Queensland, Australia, and colleagues. "It is possible that
a more successful approach to desensitization therapy using an NMDA antagonist such as
ketamine requires a more individualized stepwise tailoring of the dosage (i.e., infusion
rate) and duration of drug administration."

The authors reviewed the medical records of 33 inpatients with CRPS treated in
Queensland at least once with a continuous subanesthetic intravenous infusion of
ketamine. After the first treatment, 25 patients (76%) had complete pain relief, six
patients (18%) had partial relief, and two patients (6%) had no relief. Of the 33 patients,
54% remained pain-free for at least three months and 31% remained pain-free for at least
six months after the first course of therapy.

Because of relapse, 12 of these patients received a second course of ketamine, and two
patients received a third course. All 12 of these patients had complete relief of their
CRPS pain. After the second treatment, 58% of 12 patients experienced relief for at least
one year, and nearly one third remained pain-free for at least three years.

The most frequently observed adverse effect was a feeling of inebriation. Six patients had
hallucinations, and four patients had changes in liver enzymes that resolved when the
infusion was terminated. Less frequent adverse effects were lightheadedness, dizziness,
and nausea.

"This retrospective review suggests that limited subanesthetic inpatient infusions of

ketamine may offer a promising therapeutic option in the treatment of appropriately
selected patients with intractable CRPS," the authors write. "More study is needed to
further establish the safety and efficacy of this novel approach."

While awaiting further data, the authors recommend limiting the duration of a continuous
ketamine infusion treatment to a maximum of four to five days, limiting the maximum
infusion rate to about 25 to 50 mg per hour, and combining ketamine with
a suitable neuroprotective agent.
Pain Med. 2004;5(3):263-275

Reviewed by Gary D. Vogin, MD

Related Links
Conference Articles
The Use of Topical Analgesics in the Treatment of Neuropathic Pain: Mechanism of
Action, Clinical Efficacy, and Psychologic Correlates
Resource Centers

Advanced Approaches to Chronic Pain Management Resource Center

Pharmacologic Management of Pain Resource Center

Laurie Barclay, MD is a freelance reviewer and writer for Medscape.

Medscape Medical News 2004. © 2004 Medscape

Send press releases and comments to news@medscape.net.

• About Medscape • Privacy & Ethics • Terms of Use • WebMD Health• WebMD
Corporate • Help
All material on this website is protected by copyright, Copyright © 1994-2007 by
Medscape. This website also contains material copyrighted by 3rd parties. Medscape
requires Microsoft browsers in versions 6 or higher.

77777888888888888888888888888888

Criteria for Diagnosing

Complex Regional Pain Syndrome Type I (RSD)

 The presence of an initiating noxious event, or a cause of immobilization
 Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to
any inciting event
 Evidence at some time of edema, changes in skin blood flow (skin color changes, skin
temperature changes more than 1.1°C difference from the homologous body part), or
abnormal sudomotor activity in the region of the pain
 This diagnosis is excluded by the existence of conditions that would otherwise
account for the degree of pain and dysfunction

Complex Regional Pain Syndrome Type II (Causalgia)

 The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not
necessarily limited to the distribution of the injured nerve
 Evidence at some time of edema, changes in skin blood flow (skin color changes, skin
temperature changes more than 1.1°C difference from the homologous body part), or
abnormal sudomotor activity in the region of pain
 This diagnosis is excluded by the existence of conditions that would otherwise
account for the degree of pain and dysfunction.

ket

ketamine case study unusccessful Pain pract., Volume 7(1).March 2007.39–43.htm