Question

Opioid analgesics mimic endogenous opioids by activating opioid receptors in the central and peripheral nervous systems to produce analgesia, respiratory depression, sedation and constipation. The product information for morphine indicates the following information:

“Chronic use of opioid analgesics may be associated with the development of physical dependence.”

Discuss this statement including a simple explanation (e.g. that could be understood by an individual without expertise in pharmacology) of what this statement means, examples of physical dependence effects that may be anticipated for opioids specifically, and ONE strategy that could be utilised to minimise the detrimental effects of physical dependence. Please clearly highlight the reasoning underlying your answers. (NOTE: this is worth 8 marks, so will require a detailed explanation)

Answer 1

Opioids bind to the opioid receptors i the brain, Gastrointestinal tract and spinal cord. Some of those are endogenous which are produced by the body called 'Endorphin'. Exogenous opioids are derived from environment like Heroin, morphine that are derived from opium poppy plant. Fentanyl is synthetic drug of opioid which is synthesized in the laboratory.

• How opioid works?

They are acting on the opioid receptors of the brain nerve tissues. Normally in the absence of endorphins, inhibitory neuron secrete a neurotransmitter that prevents the nearby neurons from releasing the neurotransmitter dopamine.

When the body is involved in vigorous exercise, it induces release of endorphins, to the opioid receptors present on the inhibitory neurons. As these binds to the receptors, they inhibit the neurons from releasing the inhibitory neurotransmitters, allowing the dopamine secreting neurons to freely unload dopamine. The dopamine then will be picked up by the third neuron in the same area. When dopamine release takes place in the pain processing regions of the brain like thalamus, brainstem and spinal cord, the result is feeling less pain. When dopamine release take place in the reward pathway regions present in the ventral tegmental area, nucleus accumbens and prefrontal cortex the result is a calming effect.

When a powerful exogenous opioid binds to the opioid receptors ,it allows a massive flow of dopamine. This helps in pain control. It can also cause an incredible state of euphoria which is an emotion of floating in the air. The-us providing a dopamine mediated pleasure. When the opioid continues this pathway, the brain will be in this state over again and again. Exogenous opioids have multiple ways to reach the brain.

• By ingestion: slowest acting way
• Inhalation: faster action. Drugs are rapidly absorbed through the lungs.
• Injection into the blood stream. : Fastest way to reach in the bran.

Over-usage of these drugs create a tolerance. That is the reduced response due to repeated use. Hence an increased dosage is needed to get the original response.

This might happen due to :

1. Opioid receptors will become less sensitive to the drug.
2. The neurons will remove the drug from the receptors in a process known as 'down regulation'.

• Tolerance remains for a long time even after tapering the drug. In a normal man, the homeostasis maintains a normal heart beat, blood pressure and wake fullness. In a repeated opioid abuser, the heart rate, blood pressure and wakefulness will be increased when the drug is not got. This is known as 'withdrawal symptoms'. The symptoms are so much frustrating that the person must get the drug to make the body's homeostasis to normal. Thus the patient will become a dependent on the drugs. Increased blood pressure, anxiety, shivering, tremors, yawning, body pain, sweating, sneezing, running nose, abdominal cramps, diarrhea, vomiting, increased heart rate. These symptoms Promote them to use opioids again. Negative reinforcement is the removing of drug which causing withdrawal symptoms which reinforces more drug use to avoid those symptoms. There is positive reinforcement too. The drug use will cause euphoria which will promote to take more drugs. Both negative and positive reinforcement causes the drug addiction.

Opioid use disorder can be diagnosed by the presence of any two of the following conditions in one year:

1. Using more or for longer than intended
2. Unable to cut down
3. Significant amount of time
4. Cravings to use opioids.
5. Affect responsibilities.
6. Causes recurrent inter-personal problems.
7. Giving up important activities.
8. Using in physically dangerous situations.
9. Worsen the physical or psychological problems.
10. Tolerant to opioids.
11. Withdrawal symptoms from opioids.

• Having 2-3 off the above symptoms : MILD
• Having 4-5 off the above symptoms: MODERATE
• 6 or more: SEVERE

In addition to ruining a person's normal life it can cause over dosage issues too. In most cases over dosage of opioids causes cardiac and respiratory depression. They will have pinpoint pupils and stoppage of breathing. The treatment is given by providing rescue breathing, supplemental oxygen and administering Naloxone.

Treatment of over dosage:

NALOXONE is an opioid antagonist that binds powerfully to the opioid receptors. It also blocks other opioids from binding the opioid receptors. When Naloxone is injected intravenously, it can reverse the effect of opioids within minutes potentially saving one's life. High doses of strong opioids have greatest risk of addiction and death. Opioids along with other drugs that cause respiratory depression(e.g. Benzodiazepine) have greater risk of overdose because it has a synergistic effect on the respiratory depression.

Since opioids have strong chances of addiction, its use should be limited. They have a role in controlling acute pain. But the drug should be a short acting opioid at the lowest effective dose for a few days and slowly increase the dose only as needed.

When opioids are used for chronic pain, they should be used in weaned off as soon as possible. (10% DOSE PER WEEK). There are non-opioid approaches including exercise, biofeedback, use of other medications like Acetaminophen(Paracetamol) and NSAIDs(e.g. Ibuprofen).

Treatment of dependence:

For the patients with opioid dependence, the proper treatment is by therapy combined with medication.

1. Therapy includes Motivational interviewing to understand why they want to stop, and identify specific barriers for the treatment.
2. Also cognitive behavioral therapy can be used to learn about the withdrawal, discuss thoughts/feelings/behaviors that led to opioid usage, and create a plan to navigate triggers for usage.
3. Another part of therapy is the Peer support programs. This includes group discussions to avoid opioid usage and work by holding each other accountable.

In addition to therapy, medications are used that decrease the cravings and withdrawal symptoms.

• METHADONE: A full opioid agonist which have a long half-life that slowly build up in tissues allowing it to reach in a steady state within a week. Steady state is referred to that state when the overall intake of the rug is more or less equal to the elimination so that body is exposed to a stable level.
• BUPRENORPHINE: It is a partial opioid agonist, prescribed along with Naloxone which is an antagonist.

These medications can competitively bind to the opioid receptors without creating more euphoria. This approach of slowly tapering the use of opioids is much better to succeed over just stopping opioids outright.

• NALTROXONE: A medication that can be used in patients who are already abstaining from the active opioid use. This drug is an opioid antagonist that blocks the effects of opioids. All these treatment approaches will be successful in those whos are in strong support with the family and friends.