Morphine Derivatives

Welcome to the 4th addition of the Team Opioids blogs. This week's topic will cover the opiate drug, Morphine.

History of Morphine

Morphine was discovered in 1803 in Germany by Freidrich Serturner. Serturner was curious of the medicinal properties of opium and isolated the organic alkaloid compound of morphine from the opium poppy. Morphine was a popular medicine for 18th century physicians for its ability to relieve pain and provide relaxation to those who take it. It was also prescribed as a cure for alcoholism. With its positive factors, "patent medicine" were produced using morphine as an ingredient. Some products were made from more than 50% morphine. During the Civil War, opiates were used as the primary analgesics to treat injured soldiers. Opium, laudanum, paregoric, and morphine salts were used to treat pain and entering of diseases. The significant use of opiates eventually led to morphine addiction, thus the soldiers were known as "opium eaters" or "morphinists". The addiction later led to the restrictive use of opiates.

Use of Morphine

Morphine is commonly used for its analgesic properties in relieving pain. It comes in two forms: liquid and tablet. They can be administered via intramuscular, intravenous, subcutaneous, or oral. Dosage for analgesic effect is approximately 10mg, as compared to 60mg to 80mg in meperidine, a man made morphine. Onset of analgesia occurs within 5-20minutes following intramuscular administration and peak effect at 60 minutes. New epidural morphine can provide up to 48 hours of analgesia with a single injection.

Morphine acts as an agonist at μ-receptors. Perception of pain is altered as it travels to the reward centers, located in the brain and spinal cord. Thus leading to inability to feel pain. Alterations in mood, dysphoria, euphoria, relief from headaches are some of the effects of morphine use.

Morphine sulfate is a white crystalline power (white cubical mass) and is soluble in water.

Dangers of Morphine Addiction

Tolerance level can be built up over sequential use of morphine. As tolerance to morphine is established, the level of analgesic effect between each dosage will decrease thus leading to an increased dosage to achieve the same pain relief as the initial dosage. Withdrawal includes nausea, chills, tremor, diarrhea, etc. Babies born from morphine-using mothers will also go through morphine withdrawal due to crossing of the placental barrier.

Detox from morphine addiction is extremely dangerous. Physical and emotional traumas can cause stroke, heart attack and death. Methadone is used to control the morphine addiction withdrawal but people will typically acquire an addiction for methadone on top of morphine addiction. Thus the best way to get off morphine is to go cold-turkey (stop using the drug without help from other drugs or medications). This ensures no opportunity of having a "mixed addiction", being addicted to a new drug while getting off an old one.

There are cases where morphine is used as a substitute for illicit heroin or as a form of treatment for heroin dependence. The substitute for morphine addiction itself is usually a narcotic with similar analgesic effect, sometimes Demerol.

M and MJ: Morphine and Michael Jackson

In 1997, Michael Jackson released the remix album Blood on the Dance Floor: HIStory in the Mix. Although it is the best selling remix album ever released, this album contains one of the controversial songs in Jackson's career. "Morphine", centralizes on the theme of drug usage of Demorol and morphine. Demorol, generically known as meperidine hydrochloride, is a man-made synthetic compound with similar analgesic effect as morphine. This drug is prescription only and distribution is strictly controlled.

Throughout the song, Jackson made many references to morphine and Demorol in the lyrics. Critics have commented his song to be sung from the perspective of the drug itself. Others say it foreshadows Jackson's ongoing drug addiction. Unfortunately, Michael Jackson passed away on June 25, 2009 after suffering cardiac arrest.

Video of Interest

To further your knowledge of the topics from past weeks, please take the time to watch this educational video, Illegal Drugs and How They Got That Way - Opium, Morphine, & Heroin, from The History Channel.

References

Remember to vote in the box on the left. Comments are greatly appreciated.
The 5th and final addition to the Team Opioid blog will be added next week.
Please stay tuned for it.

Chronic Pain

Definitions
“Pain is a basic biological warning mechanism, signaling [actual or potential] tissue damage and physiological harm” (Field & Swarm, 2008, p.1). Acute pain lasts less than 6 months in duration, is associated with tissue damage, for the most part, the cause of the pain is known, and with treatment the pain disappears. Examples of acute pain include fractures, sprains, puncture wounds, and childbirth. In contrast, chronic pain lasts longer than 6 months and the cause of pain may not be known. Chronic pain can be benign pain or progressive pain with the former involving pain that varies in severity (eg. chronic low back pain, myofascial pain) and the latter involving pain that increases in severity over time (eg. cancer, rheumatoid arthritis). In 1999, around 100 million Americans suffered from chronic pain.

How do we feel pain?
Pain receptors are known as nociceptors that are free nerve endings found in almost every tissue in the body. Nociception involves the detection and transmission of pain signals from the site of damage to the central nervous system. More specifically, nociceptors are located at the distal end of sensory neurons where they send messages to the spinal cord’s dorsal horn using nerve fibres. At the site of pain there are chemicals such as prostaglandins, histamine, bradykinin, and serotonin which are believed to excite nociceptors which increase pain sensations. Thus, by decreasing these chemicals, pain perception is reduced.


A Sensory Neuron

Effects of Chronic Pain
Chronic pain disrupts all aspects of life including one’s mood and behaviour. Suffers of chronic pain may experience depression, anxiety, a feeling of helplessness, restricted activity, sleep deprivation, and social withdrawal. Also, chronic pain may be associated with job loss, and alcohol or substance abuse.

Types of Chronic Pain
Chronic low back pain is the most common which can arise from muscle tightness, narrowing of the spinal cord, fractures to the spine, and infections. Arthritis is manageable but not curable. It involves osteoarthritis which is a degenerative join disease in which the cartilage protecting the bone becomes damaged. Another type of arthritis includes rheumatoid arthritis which involves inflammation of the lining of the joint. Fibromyalgia is another type of chronic pain disease which is associated with tenderness, fatigue, and cognitive dysfunction.





Management of Chronic Pain
Chronic pain is often incurable due to the inability to identify the source or cause of pain and the complexity of the neurobiology of pain. Also, there are no objective tests for chronic pain as studies only involve self-reports. For optimal treatment designed to increase an individual’s quality of life, a multidisciplinary approach is best as chronic pain is complex. Positive social support and a therapeutic patient-practitioner relationship are essential for the effectiveness of chronic pain management.



Medical Treatments

1) Analgesic medications include:

Nonopioid analgesics (acetaminophen, aspirin, nonsteriodal anti-inflammatory drugs), are used for mild to moderate chronic pain but have potential toxicities. Aspirin is linked with gastrointestinal toxicity but is effective in controlling pain related to osteoarthritis and rheumatoid arthritis. Aspirin inhibits the synthesis of prostaglandins (pain chemicals) and has anti-inflammatory properties. Acetaminophen (Tylenol, Datril) works in the same manner as aspirin and has similar properties to aspirin except it is not an anti-inflammatory and it does not cause gastrointestinal problems.

Opioid analgesics (morphine, codeine, hydromorphine, fentanyl, methadone), involve natural narcotics, semisynthetic and synthetic narcotics, and endogenous opioids. They are effective in reducing moderate to severe dull chronic pain but potent opioids can only reduce pain by around 20-30%. Narcotics bind to opiate receptors (mu, delta, kappa), primarily the mu receptor, in the nervous system and inhibit nociceptor transmission. Adverse effects of opioid analgesics include impotence and loss of libido due to decreases sex hormone release, sweating or chills, physical dependence, and opioid addiction (less with adults who have no record of substance abuse, risk is 1 in 100 or 1 in 1000). Methadone has a long half-life (12-16 hrs), is inexpensive, and may reduce tolerance effects but if taken more than once a day, the drug could accumulate, resulting in dangerously high plasma levels.

Adjuvant analgesics (anticonvulsants, anti-depressants), work well for neuropathic pain but only have modest analgesic efficacy. Benefits include pain relief, insomnia relief, control of irritability, and management of depression and anxiety. Best anticonvulsants include gabapenin and pregablin. The best studied antidepressant for pain relief includes amitriptyline.

2) Localized injections- decrease neural transmission of pain signals. Spinal steroid injections are used for neck, back, and radiating arm or leg pain. It provides modest, short term pain relief that can allow the patient to do physical therapy and rehabilitation. But steroid injections can lead to toxicity, hyperglycaemia, fluid retention, and osteoporosis.



Cognitive-Behavioral Therapy (aka mind-body connections)

This approach works best if accompanied with educating the patient and their family on pain, by cognitively restructuring negative states associated with pain, by changing behaviour through positive reinforcement, by setting short and long term realistic goals for the patient, by pacing daily activities, by learning good communication skills, and by improving sleeping habits.

1) Breathing techniques-slow deep breathing (belly breathing) helps refocus attention, slow metabolism, and reduce tension.

2) Progressive and passive relaxation- progressive involves alternately tensing and relaxing muscles whereas passive relaxation involves observing a certain muscle group and allowing it to relax and reduce tension.


3) Meditation-slow breathing, muscles relax, and focus on present moment.

4) Guided Imagery (self or therapist guided)- when breathing has slowed, imagery is introduced.

5) Hynosis- requires curiosity and willingness. It is a heightened state of awareness that is not sleep, and helps in relaxation and narrowing attention field.

6) Biofeedback- a device that allows patients to become aware of physiological body processes. Thermal biofeedback involves a temperature sensor that helps patients learn to warm their hands and raise their peripheral temperature as cold hands are related to stress and body tension.



Physical Therapy

Inactivity results in muscle tone loss and exercise becomes more painful as the muscles become deconditioned. The goal of physical therapy is to gradually increase strength, flexibility and endurance without increasing pain. This, in turn, can improve sleep and energy, and help with weight loss which can help reduce the strain on painful joints.



Complementary and Alternative Therapies

Complementary therapies work with conventional therapies while alternative therapies are used in place of conventional therapies. Alternative therapies include homeopathic and naturopathic therapies. Complementary therapies include herb and dietary supplements (eg. omega 3 fatty acids help with inflammatory forms of arthritis), manipulation therapies (massage, chiropractic treatment, osteopathy), and energy therapies (acupuncture, reiki, magnetic therapy). Energy therapies believe that flow of energy in the body can be unbalanced which can have negative effects on the body and energy therapies allow for the energy to be rebalanced. Acupuncture works by inserting needles into points in the body which, in turn, release blocked energy flow to restore balance. Reiki involves the flow of energy from practitioner to patient through light touch. Osteopathy involves manipulating the muscles and joints to help the body fight illness and heal. Spinal decompression is another complementary therapy that is targeted at treating back pain.


Spinal Decompression Video
(Go to video titled "Non-surgical relief")


Applying what you’ve learned

Pretend you are a practitioner that needs to help a patient manage their chronic pain. What would you recommend after reading Joey’s story?

Joey is a 52 year old married man who has developed back pain after a fall from work which ruptured a disk. He underwent lumbar spinal surgery but he continues to experience an aching, grinding pain in his low back. This injury hasn’t allowed him to work, which means he spends most of his day watching TV with little to no exercise. He has been on a number of pain medications that have only been mildly effective and his wife claims that he is depressed as well as stressed over his current condition.

Possible regimen: educate Joey and his family on his condition and how they can provide positive support, injection therapies, antidepressants as well as cognitive restructuring of negative pain related thoughts, individualized physical therapy, cognitive-behavioural therapies, complementary therapies like acupuncture and spinal decompression.

References

Heroin

An Introduction to Heroin
An incredible controversial drug, heroin has an interesting history, one that has taken thousands of years, and still is playing it’s part in our worlds history. It’s been an instigator of a wars (war on drugs), and has destroyed many lives. Hopefully after reading this blog, you’ll have a better idea on what heroin was, is, and does.

Heroin’s History
Opium poppies were first harvested in lower Mesopotamia as far back as 3400 BC. It was referred to as the Hul Gil, or the “joy plant”. The skill of poppy cultivation would be passed along to the Assyrians, who would pass it to the Babylonians, who then passed it onto the Egyptians. In 1300BC in the capitol of Thebes, the opium trade grew until; the drug was traded across the Mediterranean Sea into Greece, Carthage, and Europe.

Hippocrates, “the father of medicine”, saw usefulness in its ability as a styptic for internal disease and the ability to treat diseases of woman and epidemics.As time passed, opium actually disappeared from European records for a few hundred years; it wasn’t until the 1300’s that opium became a taboo subject for people of knowledge during the Holy Inquisition. This was because anything from the east was seen as linked to the Devil.

It wasn’t until the 19th century that the chemical analysis for opium was discovered, this being two alkaloids, codeine and morphine. Heroin or, Diacetylmorphine, was first synthesized by C. R. Alder Wright in 1874 who was working for St. Mary’s Hospital. He did this by combining different acids with Morphine.
He boiled anhydrous morphine alkaloid with acetic anhydride for several hours and produced a more potent, acetylated form of morphine

Bayer ,better know as the makers of Aspirin, started producing Diamorphine, and sold it around the world for prescription purposes, that was labeled non addictive substitute for morphine(they actually went as far as saying that it cures morphine addiction) and a cough suppressant. Bayer ended up calling this miracle product Heroine, the name comes from the German word “heroisch” and was chosen because of the heroic feeling it gave you. Funnily enough, this new product was found to rapidly metabolize into morphine when processed in the body, making it a quicker acting form of morphine. This was incredible embarrassing for the company and become a historical blunder.

Heroin is now used as a pain killer, and a recreational drug. The chance for addiction and abuse is extremely high with chronic use being associated with a medium physical dependence, and a high psychological dependence.

Currently heroine is cultivated from the poppy plant, being produced in Afghanistan, Thailand, and other parts of South East Asia; Afghanistan being the biggest producer with 87% of the worlds heroine supply. The peak of production in Afghanistan was in 1999, when 350 square miles. (This is roughly 4 times the size of the city of Vancouver) This was changed in 2001 when the Taliban outlawed poppy cultivation which cut production by 94%. In 2001 only 30 square miles were used for poppy cultivation. A year later British and American troops removed the Taliban from power; people leapt at this chance, increasing poppy production to 285 square miles. In current times, cultivation of poppies has exploded even further, reaching an all-time high in 2006, war seemingly being the catalyst for this.

Currently heroine is illegal in most countries, some such as, Malaysia, Singapore, and Thailand giving the death penalty for trafficking in heroin, this can include people from other countries that the death penalty doesn’t apply.

How Heroine works

Heroin, or diacetylmorphine, is a semi-synthetic opioid drug, it’s synthesized from morphine which is derived from opium poppies. The white crytalized form is known as hydrochloride salt diacetylmorphine hydrochloride.

When used orally, heroin goes through first-pass metabolism, this means that concentration of the drug gets greatly reduced; However, when it is injected, it avoids this process and easily moves past the blood brain barrier, due to the presence of acetyl groups, which make it more lipid-soluable then even morphine. Once in the brain heroin gets deacetylated into 6-monoacetylmorphine (6-MAM) and morphine which bind to μ-opioid receptors

The short term affects of heroin happen quickly, and last for a few hours. The user will feel euphoric, users report that they feel warm and flushed. After the effects of the euphoria wear off, users go “on the nod,” an almost sleepwalking state of mind. Users are unable to think properly due to the depression of the central nervous system. Some side effects include slurred speech, vomiting, impaired night vision, droopy eyelids, and constipation/ anal leakage.

Using the name diamorphine, heroin is prescribed in certain places, such as the United Kingdom, where its used as an analgesic. Usually it’s administered subcutaneously, intramuscular, intrathecal, or intravenously In other countries usually strong opiates or morphine are used instead.


Some facts about Heroin abuse
Between 1990 and 2000 heroin abuse has risen from 182 to 1067 among 12-17 years old, and from 4654 cases to 18400 with 18-25 year old. (Drug Abuse Warning Network, 2002)

At substance abuse centers, Heroin admissions has increased 44 percent between 1992 and 2000 (Drug and Alcohol Services Information System[DASIS], 2003).

Half of repeated abusers of heroin will become addicts. (Doweiko, 2005)

Most persons who abuse heroin show signs of dysfunctionality at an earlier age (Ray & Ksir, 2004).

Heroin abuse can have a physiological component to it, where heroin abuse can be both acute and chronic.

Abusing Heroin has shown to be lethal. Perhaps the most dangerous effect being overdosing following a period of reduced use. (Warner-Smith, Darke, Lynskey, & Hall, 2001).

Conditional tolerance is a phenomenon where state dependence happens; this means that administering the same dose of heroin in a new environment will cause reduced tolerance and as a consequence a greater chance of OD. (NIDA, 2002).

Since Heroin is a intravenous (IV) drug, users may share needles. Almost a third of all people infected with HIV and AIDS in North America are IV drug users.

Steriotypical Heroin Users, those being from urban settings, people that are disadvantaged, or unemployed used to dominate the percentage of heroin users, lately that has changed and the amount of middle class and rural users has grown. Heroin abuse isn’t limited to lower income users anymore and is a drug with no preference. (Epstein & Gfroerer, 2003).

Heroin also seems to effect short and long term memory, causes Decreased attention spans, poorer information processing ability, and lower critical thinking skills, in comparison to non heroin users using cohort measurements. (Darke, Sims, McDonald, & Wickes, 2000).

A person who is addicted to heroin could possible inject the drug every three to four hours for 365 days a year; This would total 1300 injections. This can accumulate to incredible high cost even though heroin is relatively cheap. This Is why heroin user with no other means of getting disposable income resort to crime to pay for there addiction. (Hammersley & Morrison, 1987).



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