Re: Pain ladders and how they administer medications

[Guest guest]

> Jeanne B wrote:

> Holy cats, Steve M! I had no idea about Tramadol. Oh my gosh. The

> kathunk you just heard was me hitting my head on the keyboard.

ttp://hab.hrsa.gov/deliverhivaidscare/clinicalguide11/cg-801_pain.html

STEVE, Jeanne

Got to call you on this one and Tramadol, ULTRAM is an opioid antangaist and NOT

an anti depressant (accepted one) but one of the first line of medications on

the pain ladder and has stipulations as an antagonist it will lessen the pain

performances of other opioids so it should not be should used as a break thru

medication as my pharmacist and pain research physician has said. So the World

Health Organization has included it on the list rung. It is considered by the

World Health Organization as an opioid and as other opioids some can be called

in Vicodin etc.

I want to clarify it is not approved as an anti depressant and copied this from

Wikipedia for those to understand as I took this for years as a break thru and

it was weaken or an antagnonist my other med. Also it is on the WHO, World

Health Organization ladder as opiate.

Wikipedia, the free encyclopedia

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Tramadol

Systematic (IUPAC) name

(1R,2R)-rel-2-[(dimethylamino)methyl]- 1-(3-methoxyphenyl)cyclohexanol

Clinical data

Trade names Ryzolt, Ultram

AHFS/Drugs.com monograph

MedlinePlus a695011

Pregnancy cat. C(AU) C(US)

Legal status Prescription Only (S4) (AU) POM (UK) â„ž-only (US) â„ž Prescription

only

Routes Oral, IV, IM, rectal, sublingual, buccal, intranasal

Pharmacokinetic data

Bioavailability 68–72%(Increases with repeat dosing.)

Protein binding 20%

Metabolism Hepatic demethylation and glucuronidation

Half-life 5.5–7 hours

Excretion Renal

Identifiers

CAS number 27203-92-5

ATC code N02AX02

PubChem CID 33741

DrugBank DB00193

ChemSpider 31105

UNII 39J1LGJ30J

KEGG D08623

ChEMBL CHEMBL1066

Chemical data

Formula C16H25NO2

Mol. mass 263.4 g/mol

SMILES eMolecules & PubChem

InChI[show]

•

(what is this?) (verify)

Tramadol hydrochloride (Ultram, Tramal) is a centrally acting synthetic opioid

analgesic used in treating severe pain. The drug has a wide range of

applications, including treatment for Rheumatoid arthritis, restless legs

syndrome and fibromyalgia. It was developed by the pharmaceutical company

Grünenthal GmbH in the late 1970s.[1][2]

Tramadol possesses weak agonist actions at the μ-opioid receptor, releases

serotonin, and inhibits the reuptake of norepinephrine.[3][4]

While its action is not like that of other opioids, Tramadol is a synthetic

analog of the phenanthrene alkaloid codeine. Tramadol is converted to

O-desmethyltramadol, a significantly more potent μ-opioid agonist. Opioids are

chemical compounds which act upon one or more of the human opiate receptors. The

euphoria and respiratory depression of opioids are mainly caused by the μ1 and

μ2 receptors; the addictive nature of tramadol, as well as other opioids, is

due to these effects, but tramadol's serotonergic and noradrenergic effects may

contribute to possible dependence as well.[citation needed] The opioid agonistic

effect of tramadol and its major metabolite(s) are almost exclusively mediated

by the substance's action at the μ-opioid receptor. This characteristic

distinguishes tramadol from many other substances (including morphine) of the

opioid drug class, which generally do not possess tramadol's degree of subtype

selectivity.

Contents

[hide]

• 1 Medical uses

• 1.1 Availability and usage

• 1.2 Investigational uses

• 2 Adverse effects

• 2.1 Physical dependence and withdrawal

• 2.2 Psychological dependence and recreational use

• 2.3 Detection in biological fluids

• 3 Mechanism of action

• 4 Chemistry

• 4.1 Characteristics

• 4.2 Comparison with related substances

• 4.3 Synthesis and stereoisomerism

• 5 Metabolism

• 6 Legal status

• 7 Proprietary preparations

• 8 Veterinary medicine

• 9 References

• 10 External links

[edit] Medical uses

Tramadol is used similarly to codeine, to treat moderate to moderately severe

pain.[5] Tramadol is somewhat pharmacologically similar to levorphanol (albeit

with much lower μ-agonism), as both opioids are also NMDA-antagonists which

also have SNRI activity (other such opioids to do the same are

dextropropoxyphene (Darvon) & M1-like molecule tapentadol (Nucynta, a new

synthetic atypical opioid made to mimic the agonistic properties of tramadol's

metabolite, M1(O-Desmethyltramadol). Tramadol is also molecularly similar to

venlafaxine (Effexor) and has similar SNRI effects, with antinociceptive effects

also observed. It has been suggested that tramadol could be effective for

alleviating symptoms of depression, anxiety, and phobias[6] because of its

action on the noradrenergic and serotonergic systems, such as its " atypical "

opioid activity.[7] However, health professionals have not endorsed its use for

these disorders,[8][9] claiming it may be used as a unique treatment (only when

other treatments failed), and must be used under the control of a

psychiatrist.[10][11]

In May 2009, the United States Food and Drug Administration issued a Warning

Letter to & , alleging that a promotional website commissioned by

the manufacturer had " overstated the efficacy " of the drug, and " minimized the

serious risks " .[12] The company which produced it, the German pharmaceutical

company Grünenthal GmbH, were alleged to be guilty of " minimizing " the

addictive nature and proposed efficacy of the drug, although it showed little

abuse liability in preliminary tests. The 2010 Physicians Desk Reference

contains several warnings from the manufacturer, which were not present in prior

years. The warnings include more compelling language regarding the addictive

potential of tramadol, the possibility of difficulty breathing while on the

medication, a new list of more serious side effects, and a notice that tramadol

is not to be used in place of opiate medications for addicts. Tramadol is also

not to be used in efforts to wean addict patients from opiate drugs, nor to be

used to manage long-term opiate addiction.

[edit] Availability and usage

100mg tramadol injection, marketed by the original 'Contramal' trade-mark owner,

Grünenthal GmbH.(Hungarian release)

50 mg Tramadol HCl tablets (generic Ultram) marketed by Akyma Pharmaceuticals.

Immediate release tramadol HCl is available in many generic preparations.

Bottle of 30 tablets of 200 mg extended-release tramadol HCl (generic Ultram ER)

marketed by Patriot. Extended-release tramadol is commonly available in 100,

200, and 300 mg strengths to be taken once daily. It is often prescribed with

tramadol-APAP (Ultracet) or regular immediate-release tramadol HCl

(Ultram/Tramal/Rybix) for breakthrough pain.[13]

Tramadol is classified as a central nervous system drug usually marketed as the

hydrochloride salt (tramadol hydrochloride); the tartrate is seen on rare

occasions, and rarely (in the US at least) tramadol is available for both

injection (intravenous and/or intramuscular) and oral administration. The most

well known dosing unit is the 50 mg generic tablet made by several

manufacturers. It is also commonly available in conjunction with APAP

(paracetamol, acetaminophen) as Ultracet, in the form of a smaller dose of 37.5

mg tramadol and 325 mg of APAP. The solutions suitable for injection are used in

patient-controlled analgesia pumps under some circumstances, either as the sole

agent or along with another agent such as morphine.

Tramadol comes in many forms, including:

• capsules (regular and extended release)

• tablets (regular, extended release, chewable, low-residue and/or uncoated

tablets that can be taken by the sublingual and buccal routes)

• suppositories

• effervescent tablets and powders

• ampules of sterile solution for SC, IM, and IV injection

• preservative-free solutions for injection by the various spinal routes

(epidural, intrathecal, caudal, and others)

• powders for compounding

• liquids both with and without alcohol for oral and sub-lingual

administration, available in regular phials and bottles, dropper bottles,

bottles with a pump similar to those used with liquid soap and phials with

droppers built into the cap

• tablets and capsules containing (acetaminophen/APAP), aspirin and other

agents.

Tramadol has been regularly used in the form of an ingredient in multi-agent

topical gels, creams, and solutions for nerve pain, rectal foam, concentrated

retention enema, and a skin plaster (transdermal patch) quite similar to those

used with lidocaine.

Tramadol has a characteristic and unpleasant taste which is mildly bitter but

much less so than morphine and codeine. Oral and sublingual drops and liquid

preparations come with and without added flavoring. Also, 50mg water-soluble

tramadol tablets has strawberry-flavouring, no matter which company manufactured

it, to distinguish every, same-looking and same sized Mirtazapine sublingual

tablets, which has orange flavouring irrespective of the manufacturer. This

different flavouring is considered to be a standard. Its relative effectiveness

via transmucosal routes (i.e. sublingual, buccal, rectal) is similar to that of

codeine, and, like codeine, it is also metabolized in the liver to stronger

metabolites (see below).

The maximum dosage per day is 400 mg for oral use and 600 mg for parenteral use.

Certain manufacturers or formulations have lower maximum doses. For example,

Ultracet (37.5 mg/325 mg tramadol/APAP tablets) is capped at 8 tablets per day

(300 mg/day) due to its acetaminophen content. Ultram ER is available in 100,

200, and 300 mg/day doses and is explicitly capped at 300 mg/day as well.

Patients taking SSRIs (Prozac, Zoloft, etc.), SNRIs (Effexor, etc.), TCAs,

MAOIs, or other strong opioids (oxycodone, methadone, fentanyl, morphine), as

well as the elderly (> 75 years old), pediatric (< 18 years old), and those with

severely reduced renal (kidney) or hepatic (liver) function should consult their

doctor regarding adjusted dosing or whether to use Tramadol at all.

[edit] Investigational uses

• diabetic neuropathy [14][15]

• antidepressant [16]

• postherpetic neuralgia [17][18]

• acute opioid withdrawal management[19][20]

• antidepressant withdrawal aid (proven to be effective, especially with

withdrawal from its distant relative venlafaxine (Effexor)).[citation needed]

• obsessive-compulsive disorder [21]

• premature ejaculation[22]

[edit] Adverse effects

Probability of adverse effects[23]

Effect Probability (%)

Any adverse effect 71

Drowsiness 17

Nausea 17

Dizziness 15

Constipation 11

Headache 11

Vomiting 7

Diarrhea 6

Dry Mouth 5

Fatigue 5

Indigestion 5

Seizure[24] <1

Main side effects of tramadol. Red color denotes more serious effects, requiring

immediate contact with health provider.[25]

The most commonly reported adverse drug reactions are nausea, vomiting,

sweating, itching and constipation. Drowsiness is reported, although it is less

of an issue than for non-synthetic opioids. Patients prescribed tramadol for

general pain relief with or without other agents have reported withdrawal

symptoms including uncontrollable nervous tremors, muscle contracture, and

'thrashing' in bed (similar to restless leg syndrome) if weaning off the

medication happens too quickly. Anxiety, 'buzzing', 'electrical shock' and other

sensations may also be present, similar to those noted in Effexor withdrawal.

Respiratory depression, a common side-effect of most opioids, is not clinically

significant in normal doses. By itself, it can decrease the seizure threshold.

When combined with SSRIs, tricyclic antidepressants, or in patients with

epilepsy, the seizure threshold is further decreased. Seizures have been

reported in humans receiving excessive single oral doses (700 mg) or large

intravenous doses (300 mg). However, there have been several rare cases of

people having grand-mal seizures at doses as low as 100–400 mg

orally.[26][27][28] An Australian study found that of 97 confirmed new-onset

seizures, eight were associated with tramadol, and that in the authors' First

Seizure Clinic, " tramadol is the most frequently suspected cause of provoked

seizures " .[29] There appears to be growing evidence that Tramadol use may have

serious risks in some individuals and it is contra-indicated in patients with

uncontrolled epilepsy (BNF 59). Seizures caused by tramadol are most often

tonic-clonic seizures, more commonly known in the past as grand mal seizures.

Also when taken with SSRIs, there is an increased risk of serotonin toxicity,

which can be fatal. Fewer than 1% of users have a presumed incident seizure

claim after their first tramadol prescription. Risk of seizure claim increases

two- to six-fold among users adjusted for selected comorbidities and concomitant

drugs. Risk of seizure is highest among those aged 25–54 years, those with

more than four tramadol prescriptions, and those with a history of alcohol

abuse, stroke, or head injury.[24] Dosages of warfarin may need to be reduced

for anticoagulated patients to avoid bleeding complications. Constipation can be

severe especially in the elderly requiring manual evacuation of the

bowel.[citation needed] Furthermore, there are suggestions that chronic opioid

administration may induce a state of immune tolerance,[30] although tramadol, in

contrast to typical opioids may enhance immune function.[31][32][33] Some have

also stressed the negative effects of opioids on cognitive functioning and

personality.[34]

[edit] Physical dependence and withdrawal

Tramadol is associated with the development of physical dependence and a severe

withdrawal syndrome.[35] Tramadol causes typical opiate-like withdrawal symptoms

as well as atypical withdrawal symptoms including seizures. The atypical

withdrawal symptoms are probably related to tramadol's effect on serotonin and

norepinephrine re-uptake. Symptoms may include those of SSRI discontinuation

syndrome, such as anxiety, depression, anguish, severe mood swings,

aggressiveness, brain " zaps " , electric-shock-like sensations throughout the

body, paresthesias, sweating, palpitations, restless legs syndrome, sneezing,

insomnia, vivid dreams or nightmares, nonsense and weird thoughts, micropsia

and/or macropsia, tremors, and headache among others. In most cases, tramadol

withdrawal will set in 12–20 hours after the last dose, but this can vary.

Tramadol withdrawal lasts longer than that of other opioids; seven days or more

of acute withdrawal symptoms can occur as opposed to typically three or four

days for other codeine analogues. It is recommended that patients physically

dependent on pain killers take their medication regularly to prevent onset of

withdrawal symptoms and this is particularly relevant to tramadol because of its

SSRI and SNRI properties, and, when the time comes to discontinue their

tramadol, to do so gradually over a period of time that will vary according to

the individual patient and dose and length of time on the drug.[36][37][38][39]

[edit] Psychological dependence and recreational use

ding interventional management. Adapted from World Health Organization. World

Health Organ Tech Rep Ser. 1990;804:1-73; R. Cancer Control.

2000;7:149-156 and Krames E. Med Clin North Am. 1999;83:787-808.

An alternative acceptable approach does not require an advance through the

analgesic stepladder or a " failure " of strong opioids prior to consideration of

some intermention.

Some controversy regarding the abuse potential of tramadol exists. Grünenthal

has promoted it as an opioid with a lower risk of opioid dependence than that of

traditional opioids, claiming little evidence of such dependence in clinical

trials (which is true; Grünenthal never claimed it to be non-addictive). They

offer the theory that, since the M1 metabolite is the principal agonist at

μ-opioid receptors, the delayed agonist activity reduces abuse liability. The

norepinephrine reuptake inhibitor effects may also play a role in reducing

dependence.

It is apparent in community practice that dependence to this agent may occur

after as little as three months of use at the maximum dose—generally depicted

at 400 mg per day. However, this dependence liability is considered relatively

low by health authorities, such that tramadol is classified as a Schedule 4

Prescription Only Medicine in Australia, and been rescheduled in Sweden rather

than as a Schedule 8 Controlled Drug like opioids.[40] Similarly, tramadol is

not currently scheduled by the U.S. DEA, unlike opioid analgesics. It is,

however, scheduled in certain states.[41] Nevertheless, the prescribing

information for Ultram warns that tramadol " may induce psychological and

physical dependence of the morphine-type " . Using tramadol as recreational drug

may be preferred also because at this time, tramadol is the only opioid, that

cannot be detected by the standard urinal drug-tests, due to its atypical

binding to μ-opioid receptors.

Dependence on Tramadol has been reported to be a major social problem in the

Gaza Strip. The Hamas government has attempted to cut off supplies of the drug,

and in April 2010 burnt 2 million tablets which had been intercepted while being

smuggled into the territory.[42]

Because of the possibility of convulsions at high doses for some users,

recreational use can be very dangerous.[43] Tramadol can, however, via agonism

of μ opioid receptors, produce effects similar to those of other opioids

(codeine and other weak opioids), although not nearly as intense due to

tramadol's much lower affinity for this receptor. Tramadol can cause a higher

incidence of nausea, dizziness, loss of appetite compared with opiates which

could deter abuse to some extent.[44] Tramadol can help alleviate withdrawal

symptoms from opiates, and it is much easier to control the quantity of its

usage than street drugs.[45] It may also have large effect on sleeping patterns

and high doses may cause insomnia. (Especially for those on methadone, both for

maintenance and recreation. Though there is no scientific proof tramadol lessens

effects or is a mixed agonist-antagonist, some people get the impression it is,

while someone else might benefit being prescribed both for pain and breakthrough

pain.)[46]

Most pain ladders and other pain interventions giving pain relief relate to

" cancer of pallative care thus a problem and as I said nothing against those

with cancer pain but I am sure and have seen MS patients, Chrons patients,

Migrane pain patients and back patients, neuropathic pain patients with SEVERVE

PAIN and Dr. Forest Tenent of " the Survivaval Handbook for Intractable Pain

Patients " has been an advocate of patients getting effective pain if they have

pain along with the American Pain Foundation and have lobbied for The American

Pain Act and Pain Patients Bill of RIghts and these groups and others need our

assistance letting them know we do not like not getting pain reliief and these

" best practices " started by the State of Washington need to be squashed and the

Intractable Pain laws by upheld set up in Congress.

Llook up the Pain Ladder and most are shown for Pallative care for Cancer

Patients but intractable pain patients can be certified and receive the meds

also. I got Actiq and Fentora when needed and only used if needed and tose of us

that have itractable pain patient that have no good progress, deserve relief

also and this is discrimination by the Health Societies.

I am lucky and will contact the staff at American Pain Foundation for help or Dr

Forest Tenant for help if something happens to my plan. I do believe in

alternative care, massage therapy, heat, myofascial release and given muscle

relaxants and anti depressants if needed and the interventional injections and

procedures cause arachoidnoiditis and many probably have it that do not know it

but it is NOW in my records after interventional Doctors loved to injected me

first and said no injections-no meds. This time I said no injections-just meds

or I will report the physicians for scarrring me aove the Spinal Society and

Spine Universe states to do and they are ineffective after that (3) I had over

twenty as I was told this is common procedure. This is the anesthesologist club

and they don't tell on each other. Good Luck Bennie