Opioids

Opioid
From Wikipedia, the free encyclopedia

An opioid is a chemical that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract. The receptors in these two organ systems mediate both the beneficial effects, and the side effects of opioids.

The analgesic (pain relieving) effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as by increased pain tolerance. The side effects of opioids include sedation, respiratory depression, and constipation. Opioids can cause cough suppression, which can be both an indication for opioid administration or an unintended side effect. Physical dependence can develop with ongoing administration of opioids, leading to a withdrawal syndrome with abrupt discontinuation. Opioids can produce a feeling of euphoria, and this effect, coupled with physical dependence, can lead to the recreational use of opioids by some individuals. However, misuse of opioids in this manner is uncommon in patients prescribed opioids for the treatment of pain.

Although the term opiate is often used as a synonym for opioid, it is more properly limited to the natural opium alkaloids occurring in the resin of the opium poppy and the semi-synthetic opioids derived from them.

Classification
There are a number of broad classes of opioids:
Natural opiates, alkaloids contained in the resin of the opium poppy including morphine, codeine and thebaine, but not papaverine and noscapine which have a different mechanism of action;
Semi-synthetic opiates, created from the natural opioids, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine, diacetylmorphine (heroin), nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine;
Fully synthetic opioids, such as fentanyl, pethidine, methadone, tramadol and propoxyphene;
Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.

Some minor opium alkaloids and various substances with opioid action are also found elsewhere in nature, including alkaloids present in Kratom, Corydalis, and Salvia plants and some species of poppy aside from Papaver somniferum, and there are strains which produce copious amounts of thebaine, an important raw material for making many semi-synthetic and synthetic opioids. Of all of the more than 120 poppy species, only two produce morphine.

Amongst analgesics are a small number of agents which act on the central nervous system but not on the opioid receptor system and therefore have none of the other (narcotic) qualities of opioids although they may produce euphoria by relieving pain—a euphoria that, because of the way it is produced, does not form the basis of habituation, physical dependence, or addiction. Foremost amongst these are nefopam, orphenadrine, and perhaps phenyltoloxamine and/or some other antihistamines. The remainder of analgesics work peripherally. Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns. Paracetamol is predominantly a centrally acting analgesic (non-narcotic) which mediates its effect by action on descending serotonergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release (which inhibits release of pain mediators). It also decreases cyclo-oxygenase activity.

It has been discovered that the human body, as well as those of some other animals, naturally produce small amounts of morphine and codeine and possibly some of their simpler derivatives like heroin and dihydromorphine, in addition to the well known endogenous opioids. Some bacteria are capable of producing some semi-synthetic opioids such as hydromorphone and hydrocodone when living in a solution containing morphine or codeine respectively.

Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own. Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic opioid agonist) and its metabolite dextrorphan have no opioid agonist effects at all despite their structure similarity to other opioids, instead they are potent NMDA antagonists and sigma 1 and 2 agonists and are used in many over-the-counter cough suppressants.

Pharmacology
Main article: opioid receptor
Opioids bind to specific opioid receptors in the central nervous system and in other tissues. There are three principal classes of opioid receptors, μ, κ, δ (mu, kappa, and delta), although up to seventeen have been reported, and include the ε, ι, λ, and ζ (Epsilon, Iota, Lambda and Zeta) receptors. Alternatively, σ (Sigma) receptors are no longer considered to be opioid receptors because: they are not reversed by the opioid inverse-agonist naloxone, they do not exhibit high-affinity binding for ketamine and phencyclidine, and they are stereoselective for dextro-rotatory isomers while the other opioid receptors are stereo-selective for laevo-rotatory isomers. In addition, there are three subtypes of μ receptor: μ1 and μ2, and the newly discovered μ3. Another receptor of clinical importance is the opioid-receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to μ-opioid agonists used as analgesics. These are all G-protein coupled receptors acting on GABAnergic neurotransmission. The pharmacodynamic response to an opioid depends on which receptor it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist. For example, the supraspinal analgesic properties of the opioid agonist morphine are mediated by activation of the μ1 receptor, respiratory depression and physical dependence (dependency) by the μ2 receptor, and sedation and spinal analgesia by the κ receptor. Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as μ1 and μ2 for example) providing even more [measurably] specific responses. Unique to each opioid is their distinct binding affinity to the group(s) of opioid receptors (eg. the μ, κ, and δ opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid, such as the μ opioid receptor effects being the primary receptor response to the opioid morphine, or the κ opioid receptor residing as the primary binding receptor to ketazocine). It is this primary mechanism that allows for such a wide class of opioids and molecular designs to exist, as well as their composition of slightly differing effects and side-effects, all related to their individual molecular structure/makeup (which itself is responsible for duration of action, whereby metabolic-breakdown is the primary method of opioid duration).

Uses

Clinical use
Opioids have long been used to treat acute pain (such as post-operative pain). They have also been found to be invaluable in palliative care to alleviate the severe, chronic, disabling pain of terminal conditions such as cancer. Contrary to popular belief, high doses are not required to control the pain of advanced or end-stage disease, with the median dose in such patients being only 15 mg oral morphine every four hours (90 mg/24 hours), i.e. 50% of patients manage on lower doses, and requirements can level off for many months at a time despite the fact that opioids have some of the greatest potential for tolerance of any category of drugs.

In recent years there has been an increased use of opioids in the management of non-malignant chronic pain. This practice has grown from over 30 years experience in palliative care of long-term use of strong opioids which has shown that addiction is rare when the drug is being used for pain relief. The basis for the occurrence of iatrogenic addiction to opioids in this setting being several orders of magnitude lower than the general population is the result of a combination of factors. Open and voluminous communication and meticulous documentation amongst patient, caretakers, physicians, and chemists (pharmacists) is one part of this; the aggressive and consistent use of opioid rotation, adjuvant analgesics, potentiators, and drugs which deal with other elements of the pain (NSAIDS) and opioid side effects both improve the prognosis for the patient and appear to contribute to the rarity of addiction in these cases. In most countries the use of opioids is subject to complex legal and medical regulations.

United States
The sole clinical indications for opioids in the United States, according to Drug Facts and Comparisons, 2005, are:

1. Analgesia, i.e., to combat pain of various types and induction and the continuance of anesthesia, as well as allaying patient apprehension right before the procedure. Fentanyl, oxymorphone, hydromorphone, and morphine are most commonly used for this purpose, in conjunction with other drugs such as scopolamine, short and intermediate-acting barbiturates, and benzodiazepines, especially midazolam which has a rapid onset of action and lasts shorter than diazepam or similar drugs. The combination of morphine (or sometimes hydromorphone) with alprazolam or midazolam or other similar benzodiazepines with or without scopolamine (rarely replaced with or used alongside Compazine, Zofran or other anti-nauseants) is colloquially called "Milk of Amnesia" amongst anesthesiologists, hospital pharmacists, physicians, radiologists, patients and others. The enhancement of the effects of each drug by the others is useful in troublesome procedures like endoscopies, complicated and difficult deliveries (pethidine and its relatives and piritramide where it is used are favoured by many practitioners with morphine and derivatives as the second line), incision & drainage of severe abcesses, intraspinal injections, and minor and moderate-impact surgical procedures in patients unable to have general anesthesia due to allergy to some of the drugs involved or other concerns.
   Cough (codeine, dihydrocodeine, ethylmorphine (dionine), hydromorphone and hydrocodone, with morphine or methadone as a last resort.)
2. Diarrhea (generally loperamide, difenoxin or diphenoxylate, but paregoric, powdered opium or laudanum or morphine may be used in some cases of severe diarrheal diseases)
   Diarrhea of Irritable Bowel Syndrome (Codeine, paregoric, diphenoxylate, difenoxin, loperamide, laudanum)
3. Anxiety due to shortness of breath (oxymorphone and dihydrocodeine only)
4. Detoxification (methadone and buprenorphine only)

In the U.S., doctors virtually never prescribe opioids for psychological relief (with the narrow exception of anxiety due to shortness of breath), despite their extensively reported psychological benefits, and the widespread use of opiates in depression and anxiety up until the mid 1950s. There are virtually no exceptions to this practice, even in circumstances where researchers have reported opioids to be especially effective and where the possibility of addiction or diversion is very low — for example, in the treatment of senile dementia, geriatric depression, and psychological distress due to chemotherapy or terminal diagnosis (see Abse; Berridge; Bodkin; Callaway; Emrich; Gold; Gutstein; Mongan; Portenoy; Reynolds; Takano; Verebey; Walsh; Way).

Use of opioids in palliative care
Indications for opioid administration in palliative care include:
"Any pain of moderate or greater severity, irrespective of the underlying pathophysiological mechanism"

1. Breathlessness / shortness of breath (The largest evidence base exists for morphine.)
2. Diarrhea (Loperamide is the most widely used as it does not cross the blood-brain barrier and acts only on smooth muscle, such as in the digestive tract.)
3. Painful wounds (Topical morphine in an aqueous gel can be an effective agent as it acts on opioid receptors in damaged tissue.)[1]

Opioids are often used in combination with adjuvant analgesics (drugs which have an indirect effect on the pain). In palliative care, opioids are not recommended for sedation or anxiety because experience has found them to be ineffective agents in these roles. Some opioids are relatively contraindicated in renal failure because of the accumulation of the parent drug or their active metabolites (e.g. morphine and oxycodone). Age (young or old) is not a contraindication to strong opioids. Some synthetic opioids such as pethidine have metabolites which are actually neurotoxic and should therefore be used only in acute situations.

History
Non-clinical use was criminalized in the U.S by the Harrison Narcotics Tax Act of 1914, and by other laws worldwide. Since then, nearly all non-clinical use of opioids has been rated zero on the scale of approval of nearly every social institution. However, in United Kingdom the 1926 report of the Departmental Committee on Morphine and Heroin Addiction under the Chairmanship of the President of the Royal College of Physicians reasserted medical control and established the "British system" of control—which lasted until the 1960s; in the U.S. the Controlled Substances Act of 1970 markedly relaxed the harshness of the Harrison Act.

Before the twentieth century, institutional approval was often higher, even in Europe and America. In some cultures, approval of opioids was significantly higher than approval of alcohol.

Global shortage of poppy-based medicines Morphine and other poppy-based medicines have been identified by the World Health Organization as essential in the treatment of severe pain. However, only six countries use 77% of the world's morphine supplies, leaving many emerging countries lacking in pain relief medication.[2]. The current system of supply of raw poppy materials to make poppy-based medicines is regulated by the International Narcotics Control Board under the provision of the 1961 Single Convention on Narcotic Drugs. The amount of raw poppy materials that each country can demand annually based on these provisions must correspond to an estimate of the country's needs taken from the national consumption within the preceding two years. In many countries, underprescription of morphine is rampant because of the high prices and the lack of training in the prescription of poppy-based drugs. The World Health Organization is now working with different countries' national administrations to train healthworkers and to develop national regulations regarding drug prescription in order to facilitate a greater prescription of poppy-based medicines.[3]

Another idea to increase morphine availability is proposed by the Senlis Council, who suggest, through their proposal for Afghan Morphine, that Afghanistan could provide cheap pain relief solutions to emerging countries as part of a second-tier system of supply that would complement the current INCB regulated system by maintaining the balance and closed system that it establishes while providing finished product morphine to those suffering from severe pain and unable to access poppy-based drugs under the current system.

Adverse effects
Common adverse reactions in patients taking opioids for pain relief include: nausea and vomiting, drowsiness, itching, dry mouth, miosis, and constipation.[4]
Infrequent adverse reactions in patients taking opioids for pain relief include: dose-related respiratory depression (especially with more potent opioids), confusion, hallucinations, delirium, urticaria, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil).[4]
Opioid-induced hyperalgesia has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some palliative care patients, most often when dose is escalated rapidly. [5][6] If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. [7][8]
Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit leukocyte migration. However the relevance of this in the context of pain relief is not known.

Treating opioid adverse effects
Most adverse effects can be managed successfully. (For more complete information see [9] and the online palliative care formulary available on Palliativedrugs.com.)

• Nausea: tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3 mg once at night) are very effective. Stronger antiemetics such as ondansetron or tropisetron may be indicated if nausea is severe or continues for an extended period, although these tend to be avoided due to their high cost unless nausea is really problematic. The dopamine antagonist domperidone does not cross the blood-brain barrier, so blocks opioid emetic action in the chemoreceptor trigger zone without central anti-dopaminergic effects.
• Vomiting: if this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation) then this can be managed with a prokinetic (e.g. domperidone or metoclopramide 10 mg every eight hours), but usually needs to be started by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).
• Drowsiness: tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps. Certain opioids such as diamorphine tend to be particularly sedating, while others such as oxycodone and meperidine (pethidine) tend to produce less sedation, but individual patients responses can vary markedly and some degree of trial and error may be needed to find the most suitable drug for a particular patient.
• Itching: tends not to be a severe problem when opioids are used for pain relief, but if required then antihistamines are useful for counteracting itching. Non-sedating antihistamines such as fexofenadine are preferable so as to avoid increasing opioid induced drowsiness, although some sedating antihistamines such as orphenadrine may be helpful as they produce a synergistic analgesic effect which allows smaller doses of opioids to be used while still producing effective analgesia. For this reason some opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which may also have the added advantage of reducing nausea as well.
• Constipation: this develops in 99% of patients on opioids and since tolerance to this problem does not develop, nearly all patients on opioids will need a laxative. Over 30 years experience in palliative care has shown that most opioid constipation can be successfully prevented: "Constipation ... is treated [with laxatives and stool-softeners]" (Burton 2004, 277). According to Abse, "It is very important to watch out for constipation, which can be severe" and "can be a very considerable complication" (Abse 1982, 129) if it is ignored. Peripherally acting opioid antagonists such as alvimopan and methylnaltrexone (Relistor) are currently under development which have been found to effectively relieve opioid induced constipation without affecting analgesia or triggering withdrawal symptoms.[10][11]
• Respiratory depression: Although this is the most serious adverse reaction associated with opioid use it usually is seen with the use of a single, intravenous dose in an opioid-naive patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem. Several drugs have been developed which can block respiratory depression completely even from high doses of potent opioids, without affecting analgesia, although the only respiratory stimulant currently approved for this purpose is doxapram, which has only limited efficacy in this application.[12][13] Newer drugs such as BIMU-8 and CX-546 may however be much more effective.[14][15][16]
• Reversing the effect of opioids: Opioid effects can be rapidly reversed with an opioid antagonist (literally an inverse agonist) such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating and/or reversing the agonist effects. However, the elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required, or a longer acting antagonist such as nalmefene may be used. In patients taking opioids regularly it is essential that the opioid is only partially reversed to avoid a severe and distressing reaction of waking in excruciating pain. This is achieved by not giving a full dose (e.g. naloxone 400 μg) but giving this in small doses (e.g. naloxone 40 μg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief.

Safety
Studies over the past 20 years have repeatedly shown opioids to be safe when they are used correctly. In the UK two studies have shown that double doses of bedtime morphine did not increase overnight deaths,[17] and that sedative dose increases were not associated with shortened survival (n=237).[18] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).[19] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.[20] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.[21] The survival of Japanese patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs.[22] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).[23] Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).[24] Injections of morphine given subcutaneously to Canadian patients with restrictive respiratory failure did not change their respiratory rate, respiratory effort, arterial oxygen level, or end-tidal carbon dioxide levels.[25] Even when opioids are given intravenously, respiratory depression is not seen.[26]

Carefully titrating the dose of opioids can provide for effective pain relief while minimizing adverse effects. Morphine and diamorphine have been shown to have a wider therapeutic range or "safety margin" than some other opioids. It is impossible to tell which patients need low doses and which need high doses, so all have to be started on low doses, unless changing from another strong opioid.[9]

Tolerance
Tolerance is the process whereby neuroadaptation occurs (through receptor desensitization) resulting in reduced drug effects. Tolerance is more pronounced for some effects than for others; tolerance occurs quickly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more slowly to the analgesia and other physical side effects. However, tolerance does not develop to constipation or miosis.

Tolerance to opioids is attenuated by a number of substances, including calcium channel blockers[27][28], intrathecal magnesium[29] and zinc[30], and NMDA antagonists such as ketamine.[31] The cholecystokinin antagonist proglumide is also used to reduce tolerance to opioid drugs,[32][33][34] and newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.[35]

Magnesium and zinc deficiency speed up the development of tolerance to opioids[citation needed] and relative deficiency of these minerals is quite common[36] due to low magnesium/zinc content in food and use of substances which deplete them including diuretics (such as alcohol, caffeine/theophylline) and smoking. Reducing intake of these substances and taking zinc/magnesium supplements may slow the development of tolerance to opiates.[citation needed]

Dependence
Dependence is characterised by extremely unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued after tolerance has developed. The withdrawal symptoms include severe dysphoria, sweating, nausea, rhinorrea, depression, severe fatigue, vomiting and pain. Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms.[9] The speed and severity of withdrawal depends on the half-life of the opioid; heroin and morphine withdrawal occur more quickly and are more severe than methadone withdrawal, but methadone withdrawal takes longer. The acute withdrawal phase is often followed by a protracted phase of depression and insomnia that can last for months. The symptoms of opioid withdrawal can also be treated with other medications, but with a low efficacy. [37]

Addiction
Addiction is the process whereby physical and/or psychological dependence develops to a drug - including opioids. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug. Psychological addiction is more common in people taking opioids recreationally, it is rare in patients taking opioids for pain relief.[9] Several drugs have been shown to effectively block addiction to opioid drugs, most notably the plant extract ibogaine[38] and its newer derivative 18-Methoxycoronaridine.[39]

Misuse
Drug misuse is the use of drugs for reasons other than what the drug was prescribed for. Opioids are primarily misused due to their ability to produce euphoria.

Examples

Endogenous opioids
Dunniod-peptides that are produced in the body include:

• β-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus and in a small population of neurons in the brainstem, and acts through μ-opioid receptors. β-endorphin has many effects, including on sexual behavior and appetite. β-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. α-neoendorphin is also expressed in POMC cells in the arcuate nucleus.
• [met]-enkephalin is widely distributed in the CNS; [met]-enkephalin is a product of the proenkephalin gene, and acts through μ and δ-opioid receptors. [leu]-enkephalin, also a product of the proenkephalin gene, acts through δ-opioid receptors.
• Dynorphin acts through κ-opioid receptors, and is widely distributed in the CNS, including in the spinal cord and hypothalamus, including in particular the arcuate nucleus and in both oxytocin and vasopressin neurons in the supraoptic nucleus.
• Endomorphin acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors.

Opium alkaloids
Phenanthrenes naturally occurring in opium:

• Codeine
• Morphine
• Thebaine
• Oripavine[40]

Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.

Semisynthetic derivatives

• Diacetylmorphine (heroin)
• Dihydrocodeine
• Hydrocodone
• Hydromorphone
• Nicomorphine
• Oxycodone
• Oxymorphone

Synthetic opioids

Anilidopiperidines

• Fentanyl
• Alphamethylfentanyl
• Sufentanil
• Remifentanil
• Carfentanyl
• Ohmefentanyl

Phenylpiperidines

• Pethidine (meperidine)
• Ketobemidone
• MPPP
• Allylprodine
• Prodine
• PEPAP

Diphenylpropylamine derivatives

• Propoxyphene
• Dextropropoxyphene
• Dextromoramide
• Bezitramide
• Piritramide
• Methadone
• Dipipanone
• Levomethadyl Acetate (LAAM)
• Loperamide (used for diarrhoea, does not cross the blood-brain barrier)
• Diphenoxylate (used for diarrhoea, does not appreciably cross the blood-brain barrier)

Benzomorphan derivatives

• Dezocine
• Pentazocine
• Phenazocine

Oripavine derivatives

• Buprenorphine
• Dihydroetorphine
• Etorphine

Morphinan derivatives

• Butorphanol
• Nalbuphine
• Levorphanol
• Levomethorphan

Others

• Lefetamine
• Meptazinol
• Tilidine
• Tramadol
• Tapentadol

Opioid antagonists
Nalmefene
Naloxone
Naltrexone

See also
Psychoactive drug
Rafael Maldonado López
Opiate comparison

References

1. ^ Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle, D., Hanks, G., Cherney, I., and Calman, K., eds., Oxford University Press, 2004).
2. ^ http://www.senliscouncil.net/modules/publications/008_publication
3. ^ The World Health Organization "Assuring Availability of Opioid Analgesics" [www.euro.who.int/document/e76503.pdf]
4. ^ a b Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
5. ^ Wilson GR, Reisfield GM. "Morphine hyperalgesia: a case report." Am J Hosp Palliat Care. 2003 Nov-Dec;20(6):459–61. PMID 14649563
6. ^ Vella-Brincat J, Macleod AD. "Adverse effects of opioids on the central nervous systems of palliative care patients." J Pain Palliat Care Pharmacother. 2007;21(1):15–25. PMID 17430825
7. ^ Mercadante S, Arcuri E. "Hyperalgesia and opioid switching." Am J Hosp Palliat Care. 2005 Jul-Aug;22(4):291–4. Review. PMID 16082916
8. ^ Fine PG. "Opioid insights:opioid-induced hyperalgesia and opioid rotation." J Pain Palliat Care Pharmacother. 2004;18(3):75–9. Review. PMID 15364634
9. ^ a b c d Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
10. ^ McNicol E, Boyce D, Schumann R, Carr D. Mu-opioid antagonists for opioid-induced bowel dysfunction. Cochrane Database of Systematic Reviews. 2008 Apr 16;(2):CD006332. PMID 18425947
11. ^ Portenoy RK, Thomas J, Moehl Boatwright ML, Tran D, Galasso FL, Stambler N, Von Gunten CF, Israel RJ. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. Journal of Pain and Symptom Management. 2008 May;35(5):458–68. PMID 18440447
12. ^ Yost CS. A new look at the respiratory stimulant doxapram. CNS Drug Reviews. 2006 Fall-Winter;12(3–4):236–49. PMID 17227289
13. ^ Tan ZM, Liu JH, Dong T, Li JX. Clinical observation of target-controlled remifentanil infusion combined with propofol and doxapram in painless artificial abortion. (Chinese) Nan Fang Yi Ke Da Xue Xue Bao. 2006 Aug;26(8):1206–8. PMID 16939923
14. ^ Manzke T, Guenther U, Ponimaskin E, Haller M, Dutschmann M, Schwarzacher S, Richter D (2003). "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia". Science 301 (5630): 226–9. doi:10.1126/science.1084674. PMID 12855812.
15. ^ Wang X, Dergacheva O, Kamendi H, Gorini C, Mendelowitz D. 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function. Hypertension. 2007 Aug;50(2):368–76. PMID 17576856
16. ^ Ren J, Poon BY, Tang Y, Funk GD, Greer JJ. Ampakines alleviate respiratory depression in rats. American Journal of Respiratory and Critical Care Medicine. 2006 Dec 15;174(12):1384–91. PMID 16973981
17. ^ Regnard C and Badger C. Opioids, sleep and the time of death. Palliative Medicine, 1987; 1(2): 107–110.
18. ^ Sykes N. Thorns A. Sedative use in the last week of life and the implications for end-of-life decision making. Arch Int Med 2003: 163(3): 341–4.
19. ^ Boyd KJ. Kelly M. Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. Palliative Medicine. 1997: 11(4): 277–81.
20. ^ Good PD, Ravenscroft PJ, Cavenagh J. Effects of opioids and sedatives on survival in an Australian inpatient palliative care population. Int Med J. 2005: 35(9): 512–7.
21. ^ Hu WY, Chiu TY, Cheng SY, Chen CY. Morphine for dyspnoea control in terminal cancer patients: is it appropriate in Taiwan? J Pain & Symp Manag. 2004: 28(4): 356–63.
22. ^ Morita T, Tsunoda J, Inoue S, Chihara S. Effects of high dose opioids and sedatives on survival in terminally ill cancer patients. J Pain & Symp Manag. 2001: 21(4): 282–9.
23. ^ Chan JD et al. Narcotic and benzodiazepines use after withdrawal of life support: association with time of death? Chest. 2004: 126(1): 286–93.
24. ^ Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnoea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind control trial. Annals of Oncology. 1999: 10(12): 1511–4.
25. ^ Bruera E, Macmillan K, Pither J, MacDonald RN. Effects of morphine on the dyspnoea of terminal cancer patients. J Pain & Symp Manag, 1990: 5(6): 341–44.
26. ^ Bassam E, et al. Respiratory function during parenteral opioid titration for cancer pain. Palliative Medicine, 2007; 21: 81–86.
27. ^ Santillán R, Maestre JM, Hurlé MA, Flórez J. "Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report." Pain. 1994 Jul;58(1):129–32. PMID 7970835
28. ^ Smith FL, Dombrowski DS, Dewey WL. "Involvement of intracellular calcium in morphine tolerance in mice." Pharmacology, Biochemistry, and Behavior. 1999 Feb;62(2):381–8. PMID 9972707
29. ^ McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. "Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats." Anesthesia and Analgesia. 1998 Apr;86(4):830–6. PMID 9539610
30. ^ Larson AA, Kovács KJ, Spartz AK. "Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance." European Journal of Pharmacology. 2000 Nov 3;407(3):267–72. PMID 11068022
31. ^ Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS. "Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors." Eur J Pharmacol. 1996 Feb 15;297(1–2):27–33. PMID 8851162
32. ^ McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine. Clinical Journal of Pain. 2003 May-Jun;19(3):200–1.
33. ^ Watkins LR, Kinscheck IB, Mayer DJ. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science. 1984 Apr 27;224(4647):395–6.
34. ^ Tang J, Chou J, Iadarola M, Yang HY, Costa E. Proglumide prevents and curtails acute tolerance to morphine in rats. Neuropharmacology. 1984 Jun;23(6):715–8.
35. ^ Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opinion on Investigational Drugs. 2007 Jul;16(7):935–50.
36. ^ WHC - Magnesium Deficiency
37. ^ Hermann D, Klages E, Welzel H, Mann K, Croissant B. Low efficacy of non-opioid drugs in opioid withdrawal symptoms. Addict Biol. 2005 Jun;10(2):165–9. PMID: 16191669
38. ^ Alper KR, Lotsof HS, Kaplan CD. The ibogaine medical subculture. Journal of Ethnopharmacology. 2008 Jan 4;115(1):9–24. PMID 18029124
39. ^ Taraschenko OD, Shulan JM, Maisonneuve IM, Glick SD. 18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens. Synapse. 2007 Jul;61(7):547–60. PMID 17447255
40. ^ Odell LR, Skopec J, McCluskey A. "Isolation and identification of unique marker compounds from the Tasmanian poppy Papaver somniferum N." Forensic Sci Int (2007). PMID 17765420

External links

• American Pain Foundation
• Pain Relief Network (PRN)
• American Pain Society
• American Academy of Pain Management
• American Academy of Addiction Psychiatry, professional association of psychiatrists expert in addiction treatment
• CLiP- Current Learning in Palliative Care Fifty-six workshops on palliative care which can be used online or downloaded. Free access, no restrictions.
• International Association for Hospice and Palliative Care
• Palliativedrugs.com. Online palliative care formulary. Also has bulletin board with over 22,000 international professionals registered. Free access after registration.
• Palliative Care Matters Palliative Care information.
• Palliative Care Handbook Online palliative care textbook
• http://www.ampainsoc.org/advocacy/opioids.htm
• Merck Entry on Opioids
• Pain

Bibliography
Palliativedrugs.com Palliative Care Formulary and bulletin board with over 22,000 worldwide registered. Free to register.
Wall and Melzack's textbook of pain, 5th ed. Stephen B. McMahon and Martin Koltzenburg, eds. Edinburgh : Elsevier Churchill Livingstone, 2006.
Gutstein, Howard B. and Huda Akil, "Opioid Analgesics", in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th Edition, 2006, edited by Brunton, Laurence L., John S. Lazo, Keith L. Parker, Iain L. O. Buxton, and Donald Blumenthal.
Rossi S (Ed.) (2005). Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3.
A Guide to Symptom Relief in Palliative Care, 5th ed. Regnard C, Hockley J. Abingdon: Radcliffe Medical Press, 2004
PCF2- Palliative Care Formulary, 2nd ed. Twycross RG, Wilcock A, Charlesworth S. Abingdon: Radcliffe Medical Press, 2003.
Oxford Textbook of Palliative Medicine 3rd ed. Doyle D, Hanks G, Cherny NI, Calman K eds. Oxford : Oxford University Press, 2003.
Hanks GW. Conno F. Cherny N. Hanna M. Kalso E. McQuay HJ. Mercadante S. Meynadier J. Poulain P. Ripamonti C. Radbruch L. Casas JR. Sawe J. Twycross RG. Ventafridda V. Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. British Journal of Cancer. 2001; 84(5): 587–93.
Symptom Management in Advanced Cancer, 3rd edition. 2001. Twycross RG, Wilcock A. Abingdon: Radcliffe Medical Press.
Hanks GW. Forbes K. Opioid responsiveness. Acta Anaesthesiologica Scandinavica. 1997; 41: 154–8.
Cancer Pain Relief and Palliative Care. Geneva : WHO, 1990.
Oral Morphine, Information for Patients, Families and Friends. Twycross R., Lack S.A. Beaconsfield Publishers. 1988.

Chronic or Recurrent Pain: the Nation's Leading Cause of Disability

More than 50 million Americans suffer from chronic or recurrent pain. It's the nation's leading cause of disability and costs employers more than $60 billion a year in productivity. It can rob a person of his or her ability to work, sleep soundly, have satisfying personal relationships or enjoy the simplest of pleasures. Yet only one in four sufferers will receive proper treatment according to the American Pain Foundation.

"Pain remains one of the most undertreated ailments in society and very often pain complaints are swept under the rug," says Mark Allen Young, M.D., a physical medicine and rehabilitation specialist in Baltimore, author of Women and Pain and former editor-in-chief of the Journal of Practical Pain Management. That's because both doctors and patients tend to dismiss pain as the natural result of an injury or illness, which will end when they recover.

But keeping a stiff upper lip can be disastrous: Recent studies show that pain that lingers untreated for more than three months can actually change the hard wiring in the brain, triggering permanent changes in the way the body responds to pain signals. This both intensifies the experience of pain and risks making the condition chronic. "If pain is not nipped in the bud with aggressive treatment, it becomes much more difficult to treat," Dr. Young says.

Fortunately, a growing number of doctors recognize that pain is a debilitating medical condition in itself and sometimes must be treated separately from what triggered it What's more, some insurance companies may cover the costs of pain-management programs. And in California, to get their license renewed, physicians need to take a course in pain management, which enhances their ability to keep acute pain from becoming chronic.

If you sense that you might be developing a chronic pain problem that your current pain regimen hasn't been able to stave off, start by asking your primary-care physician to refer you to a pain specialist or clinic. If your doctor doesn't know one, look for a pain-treatment center at local hospitals or medical centers.

Although there is not one magic pill that will vanquish acute, recurrent or chronic pain, doctors now have a broad array of options that blend alternative therapies with traditional medicine. "We can't cure chronic pain," says Anthony H Guarino, M.D., a pain management specialist at the Washington University School of Medicine, in St. Louis, "but we can manage it and greatly improve a patient's quality of life."

How Pain Can Become Permanent

Once the wiring of the nervous system changes in response to prolonged pain, "the pain you feel doesn't correspond to what is going on in your body," says James N. Dillard, M.D., a rehabilitation medicine specialist in New York City and author of The Chronic Pain Solution. A few become so hypersensitive that even the slightest touch or vibration can be excruciating. "Fifteen years ago, people who had these complaints were sent to psychiatrists," says Dr. Dillard. "But now we know that the nervous system is very adaptable, and that the pain pathways can ramp up and amplify the signals."

Every person has a unique susceptibility to pain. Some people can be seriously hurt yet recover quickly, while others are incapacitated by a relatively minor mishap. "People may be genetically predisposed, or a past history of injuries may make them more susceptible," says Linda LeResche, Sc.D., an epidemiologist and professor at the University of Washington in Seattle.

Unrelenting pain can erode health and age people prematurely. The release of stress hormones in reaction to pain weakens the immune system, which compromises our ability to fight disease, A year or more of chronic pain can cause brain shrinkage that's 5 to 11 percent beyond what normal aging would take away, according to a 2004 Northwestern University study. Researchers suspect that the cumulative stress of coping with pain wears out brain nerve cells. "The long-term damage can trigger a self-perpetuating cycle of pain, making the condition more intractable," says A. Vania Apkarian, Ph.D., a pain specialist at the Northwestern University Feinberg School of Medicine, in Chicago.

Chronic pain also spawns an escalating cascade of psychological and emotional problems. Pain sufferers can't sleep, which makes them irritable, anxious, and depressed. One-third report they can't function normally and sometimes feel so bad they want to die.

To view another of my blogs, click on Maddi's Spot, or continue on with me in our study of Chronic or Recurrent Pain.

Maddi's Spot

Breaking the Cycle and Pain-Relief Resources

Breaking the vicious cycle of pain can be challenging.
"By the time patients are referred to our clinic, many of them have been in pain for five years or more," says Carmen R. Green, M.D., a pain-medicine physician at the University of Michigan, Ann Arbor. Once experts determine the source of trouble, they tailor a treatment program to a patient's medical and psychological history. Finding a pain solution is highly individual; what works for one person may not be successful for another, even when both have the same problem.

Physicians usually employ a two-step process. Unless the pain is relatively mild, they first try to soothe-or at least lessen-it with an individualized combination of painkilling drugs and other techniques. Then they create a comprehensive pain-management plan that mixes traditional and complementary therapies to help people resume to a normal life.

I. Step One: Lower the pain level. Before someone can get started on long-term strategies, his or her pain has to be at least manageable.

A. Physicians will start by reviewing a patient's current ways of seeking relief. They may try upping the dosage of medications such as ibuprofen or acetaminophen. Specific problems can call up a wide range of other drugs: antiseizure medications to ease pain triggered by nerve damage (from shingles or neuropathy from diabetes) or steroid injections for arthritis or back pain to reduce swelling, which eases pressure on nerves. Antidepressants, such as Prozac, or sleeping pills can help people in pain get a restorative night's sleep so they start to feel better during the dayl For tension headaches and migraines, doctors may use the wrinkle-eraser Botox, and injectable toxin that paralyzes cramped muscles.
B. For people in constant, severe pain, specialists turn to opiates, though many physicians are reluctant to prescribe these medications because they can be addictive and leave users nauseated and groggy. But they can soothe pain that milder drugs don't help. Doctors may try morphine, oxycodone or the longer-acting methadone, better known for weaning addicts off heroin. Skin patches containing fentanyl, another opiate, can also provide round-the-clock relief.

II. Step Two: Establish a logn-term treatment plan. Once a person's pain has been stabilized, physicians experiment with an array of treatments, depending on the condition's root cause. If they can, they wean patients off opiates, substituting less-powerful medications if still needed. Their arsenal includes a range of mainstream and mind-body strategies.

A. Mainstream Therapies. In addition to continuing some form of prescription drugs, patients may get some combination of the following:

1. Injections and nerve blocks. Local anesthetics, such as procaine, sometimes in combination with cortisone-like medicines, can be injected around nerve roots and into muscles or joints. These shots can ease swelling, irritation, muscle spasms and the abnormal nerve activity that can make people miserable.
2. Electrical stimulation. Transcutaneous electrical nerve stimulation uses a small battery-operated device that alleviates pain by externally stimulating nerve fibers through the skin. For more debilitating and intractable pain, doctors may surgically implant brain stimulators inside the spinal cord that deliver timed electrical impulses to interfere with the transmission of pain signals.
3. Physical therapy. All too often pain sufferers become sedentary because they're afraid of injuring themselves further. This contributes to weight gain and an overall physical deterioration that just exacerbates their pain. In fact, exercise may be as beneficial as heavy-duty medications at easing symptoms because it is energizing and may promote the release of endorphins, the body's natural painkillers. Doctors may prescribe exercise program, such as aquatic therapy, to get even patients crippled by agonizing pain moving again. "Regaining function is key to overcoming chronic pain," says Scott Fishman, M.D., and anesthesiologist and psychiatrist who is chief of pain medicine at the University of California, Davis, and past president of the American Academy of Pain Medicine.
4. Heat. In study of 110 men and women suffering from osteoarthritis of the knee, patients got a greater pain relief from using heat wraps that from taking ibuprofen, the usual treatment for this type of pain. "Heat wraps seem to work by blocking pain signals and they also stimulate healing by increasing blood flow," says John Mayer, Ph.D., an exercise physiologist and research director at San Diego's U.S. Spine & Sport Foundation.

B. Mind-Body Methods

1. Massage Therapy. Deep-tissue massage loosen clenched muscles and other tight tissues, which otherwise ratchet up pain. The rubbing sensation also seems to stop pain messages from reaching the brain. A 2004 study of 1,290 cancer patients at Memorial Sloan-Kettering Cancer Center, in New York City, revealed that a massage significantly reduced pain for two days or longer. "It was quite amazing," says sstudy author Barrie Cassileth, Ph.D., chief of Integrative Medicine Service at Memorial Sloan-Kettering. "human touch is
   extremely important and has physiological implications."
2. Acupuncture. The ancient Chinese therapy, which involves
   inserting very thin needles at pressure points in the skin, can ease intractable
   pain in some people. Experts don't know exactly why acupuncture works, but
   research suggests the physical stimulation triggered by the needles affects the
   nervous system and promotes the release of endorphins and other natural opiods produced by the body. Even pain caused by nerve damage, which is difficult to control with conventional pain meds, can be eased if not eliminated altogether with acupuncture, says Dr. Cassileth. In a landmark 1987 Kaiser
   Permanente study, for example, researchers compared four groups of women who had menstrual pain. They received either acupuncture, a placebo form
   of acupuncture, extra office visits or no extra treatment. Ninety one percent of
   the women in the acupuncture group cut their pain in half compared with only 36 percent of th econtrol groups. And the acupuncture patients were able to cut their use of painkillers by 41 percent in the nine months following the
   treatment. More recently a 2004 Duke University study involved 75 breast
   cancer patients who were treated wither a high tech acupuncture-like
   therapy or conventional medications to control postsurgical nausea and vomiting. A day after the procedure about three-quarters of the women who received acupuncture had no symptoms compared with half of the women who took drugs.
3. Other complementary-medicine techniques. These may divert
   sufferers' attention from pain to pleasurable thoughts. Options include
   hypnosis, meditation, music and art therapy, deep breathing and guided imagery (a method where a patient uses positive images to relieve pain.) In one 2005 study by Stanford University researchers, for example, patients were actually taught to watch their brain on pain via functional magnetic resonance imaging. Subjects saw a representation of their brain activity in the form of burning flame. They learned to make the flame fo up or down by thinking. Their pain would correspondingly go up or down. "over time, people slowly gained better control of the brain region--it is like going to a gym and working out a muscle," says researcher Sean Mackay, M.D.Ph.D., associate director of the Stanford University Pain Magagement Center, in Stanford, California. "These research results lend further validation to many of the techniques that pain psychololgists use, such as guided imagery and stress reduction, to bridge the mind-brain connection."
4. Psychological counseling. "Patients are often reluctant to see a pain psychologist because they feel doctors don't believe they have a physical problem," says Dr. Fishman. "But emotions like depression or anger can
   increase pain's decibel level." Counseling can help relieve these feelings and lower pain.

~Endoscopic Ultrasonography-Guided Celiac Plexus Block for the Management of Pain from Chronic Pancreatitis:

The natural history and pathogenesis of painful chronic pancreatitis is still poorly understood. Management of pain resulting from chronic pancreatitis can be one of the most difficult challenges a clinician faces. A variety of therapeutic options exist, including:

1. suppression of pancreatic secretion (pancreatic enzymes, octreotide),
2. symptomatic pain control with narcotics or pain modifying agents (tricyclic antidepressants, serotonin reuptake inhibitors),
3. drainage procedures (ERCP, lateral pancreatojejunostomy), and
4. surgical removal of the diseased part of the pancreatic gland (Whipple resection or total pancreatectomy).

It is clear that no one therapeutic approach works in all patients.

Unfortunately, all therapies for pain resulting from chronic pancreatitis have a variable success rate, and many patients become dependent on narcotic agents. Celiac plexus block has been used for pain relief in some patients with chronic pancreatitis. Celiac plexus block can be performed by using a blind translumbar fluoroscopic approach or by CT guidance using transposterior or transanterior approaches. The advances in endoscopic ultrasonography have allowed the development of endoscopic ultrasonography-guided celiac plexus block, a relatively simple and short (approximately 15 minutes) outpatient procedure. More importantly, paraplegia has not been described after endoscopic ultrasonography-guided celiac plexus block, probably because of the anterior transgastric approach taken during endoscopic ultrasonography-guided block, decreasing or even eliminating the risk of nerve or spinal cord injury.

A combination of long-acting local anesthetics and steroids injected into the celiac plexus under endoscopic ultrasonography guidance in patients with chronic pancreatitis has been used for years (Hawes, Personal communication, February 2002), yet the published data are scarce. Gress et al. compared endoscopic ultrasonography-guided versus CT-guided celiac blocks in a prospective, randomized fashion. The conclusion of this small study was that endoscopic ultrasonography-guided celiac block in ten patients provided more persistent pain relief than CT-guided block in eight patients. The same group of investigators recently published their prospective experience with endoscopic ultrasonography-guided celiac plexus block in 90 patients with pain resulting from chronic pancreatitis. A significant improvement in pain score occurred in 55% of the patients. The benefit persisted beyond 12 weeks in 26% of patients and beyond 24 weeks in only 10%. Younger patients (<45>

The current evidence indicates:

1. The pathogenesis of idiopathic chronic pancreatitis remains poorly understood;
2. Genetic mutations or autoimmune processes account for the minority of cases in patients with idiopathic chronic pancreatitis;
3. The true value of endoscopic ultrasonography in diagnosing small-duct chronic pancreatitis remains to be fully defined;
4. Endoscopic ultrasonography-guided celiac plexus block can provide excellent short-term pain relief in some patients with chronic pancreatitis; and
5. Until long-term studies examine the safety and efficacy of celiac plexus block, its use should be limited to treating those patients with chronic pancreatitis whose pain has not responded to other modalities.

Pain-Relief Resources:

American Academy of Pain Medicine is a professional group that offers consumers information on pain-control methods and has a directory of pain-medicine physicians. http://www.painmed.org/

American Chronic Pain Associations is a consumer group that provides pain-medicine information for professionals and patient guides that list pain-management options. ACPA sponsers more that 400 support groups nationwide. http://www.theacpa.org/

American Pain Foundation is an advocacy and education group. It offers a pain-information library, provides pain-relief resources for military veterans and online chat rooms. http://www.painfoundation.org/

The National Pain Foundation provides guides to pain-treatment strategies and links to online support groups. http://www.painconnection.org/

Good luck to all who suffer pain. May you each find a resolution.

To view another of my blogs, click on Maddi's Spot.

Maddi's Spot