Opioid Analgesic: Comparative Features & Developments
INTRODUCTION
1.1 Definition:-
The term “opioid” refers to a large group of compounds and chemicals that share the
characteristics of opium. Opium, from the Greek word “opos” for juice, refers to the liquid
collected from the unripe seed capsule of Papaver somniferum L., also known as opium poppy.
Opium has been used for medicinal purposes for centuries.1 Opioid analgesic are defined as "all of
the natural and semi synthetic alkaloid derivatives from opium, their pharmacologically similar
synthetic surrogates, as well as all other compounds whose opioid-like actions are blocked by the
nonselective opioid receptor antagonist Naloxone. Opioid analgesics, also called narcotics, are
drugs usually used for treating pain.
Opioid analgesics are prescribed for moderate to severe pain, particularly of visceral origin,
and are used in step two and step three of the analgesic ladder. Dependence and tolerance are well
known features with regular use although this should not inhibit prescribing in palliative care.
Some chronic non-malignant conditions benefit from analgesic control with opioids, but patients
should be reviewed regularly. One study showed that there has been a general increase in opioid
prescribing for a wide spectrum of non-cancer conditions. It may be appropriate to involve a
specialist in the decision to prescribe opioids long term for such conditions3.
In medicine, pain relieving agent that acts at receptor sites in the central nervous system.
Opiates are used to relieve moderate to severe pain. Drugs in this class include morphine,
Pethidine, and Diamorphine (heroin). Dependence and tolerance to these drugs can develop.4 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 effects of opioids
are due to decreased perception of pain, decreased reaction to pain as well as increased pain
tolerance Opioids can cause cough suppression, which can be both an indication for opioid
administration and 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
recreational use of opioids by many individuals.5
Opioids have played a critical role in achieving pain relief in both modern and ancient
medicine. Yet, their clinical use can be limited secondary to unwanted side effects such as
tolerance, dependence, reward, and behavioral changes.
Opioids are useful in a variety of chronically painful conditions (though they may have limited
effectiveness in some forms of neuropathic pain). For the purposes of chronic pain management,
only the oral and transdermal versions of various opioids will be considered in the following
discussion.
Pain is a crucial aspect of the body’s defense mechanisms
Pain “is a part of a rapid warning relay instruction the motor neurons of the central nervous
system to minimize detected physical harm.’’
Pain can be classified into two types
1.2.1 Acute Pain
Acute pain is short-term pain or pain with an easily identifiable cause.
Acute pain “is the body's warning of present damage to tissue or disease. It is often fast and
sharp followed by aching pain. Acute pain is centralized in one area before becoming
somewhat spread out. This type of pain responds well to medications.’’
1.2.2 Chronic Pain
Chronic pain is pain that last much longer than pain normally would with a particular injury.
Chronic pain can be constant or intermittent and is generally harder to treat than acute pain.
Pain can also be grouped by its source and related pain detecting neurons such as cutaneous pain,
somatic pain, visceral pain, and neuropathic pain Opioid Analgesics can be used to treat many
types of pain
1.2.3 What Causes Pain?
Pain is caused by the stimulation of pain receptors which are free nerve endings.
‘Nocireceptors are pain receptors that are located outside the spinal column in the
dorsal root ganglion and are named based upon their appearance at their sensory ends.’
These sensory endings look like the branches of small bushes. There are two types of
Nocireceptors that mediate fast or slow pain signals the perception of pain is when these receptors
are stimulated and they transmit signal to the central nervous system via sensory neurons in the
spinal cord.
Pain Signaling
These neurons release excitatory neurotransmitters which relay signals from one neuron to another.
The signals are sent to the thalamus, in which pain perception occurs. From the thalamus, the
signal travels to the somatosensory cortex in the cerebrum, at which point the individual becomes
fully aware of the pain.
1.3 What is Analgesia?
Analgesia simply means the absence of pain without loosing consciousness.
“The analgesia system is mediated by 3 major components : the periaquaductal grey matter
(in the midbrain), the nucleus raphe Magnus (in the medulla), and the pain inhibitory
neurons within the dorsal horns of the spinal cord, which act to inhibit pain-transmitting
neurons also located in the spinal dorsal horn..’’These areas are the areas in which the chemical
mechanisms of opioid analgesics will take place.7
1.3.1 Locations involved in Pain Signaling and Analgesia.
(1) Although the opioid (narcotic) analgesics such as morphine have proven very useful, serious
undesired effects often leads to under medication in clinical settings.
(2) The undesired effects associated with morphine include respiratory depression, tolerance,
constipation, dependence, and nausea.
Respiratory depressions the major cause of fatalities through illicit opioid use(generally with
diacetylmorphine or heroin.
(3), but such events can be generally controlled with therapeutic opiates through close observation
in a clinical setting.
The constipatory effects of morphine have been known for many years, and have proved
beneficial through its use as an anti-diarrhea agent. However, in a clinical setting, constipation
remains a major undesired effect, and the pain associated with constipation has been described as
often being worse than the pain the morphine is treating. Indeed, in extreme cases, the constipation
can be life-threatening
(4).These facts are the main reasons why chronic pain is often under medicated with morphine.
(5).Obviously, the development of novel analgesic medications lacking such deleterious effects
would prove extremely useful for physicians treating terminal cancer pain, and this manuscript will
discuss the potential approaches which can be taken by medicinal chemists in the design of agents
with a reduced profile of undesired effects. This manuscript does not attempt to present
comprehensive account of the known medicinal chemistry and pharmacology of opioids, but how
such knowledge could be applied to the discovery of new agents.8
1.4 OPIOID ANALGESIC IN PRIMARY HEALTH CARE:-
Chronic pain is a widespread and challenging problem for primary care physicians and
family physicians, particularly in patients with nonmalignant pain syndromes, who represent a
growing proportion of chronic pain diagnoses. For patients with moderate to severe acute or
chronic pain, nonopioid analgesics may not be sufficient to achieve adequate analgesia.
Historically, the use of opioids to manage pain has oscillated from broad indiscriminate use a
century ago to narrowly restricted use in subsequent decades that left too many people without
adequate analgesia. More recently, multiple forces have driven the increased use of strong opioids
in the management of pain, including an evolving regulatory outlook and increasing acceptance
from the clinical community. National legislation recognizing the importance of pain treatment has
been proposed, including an effort to establish a National Center for Pain and Palliative Care
Research.
The Agency for Health Care Policy and Research has established pain treatment guidelines,
and the Joint Commission on Accreditation of Healthcare Organizations has included pain
treatment in its evaluation of hospitals and healthcare providers. Reports on advances in pain
research in consumer media are increasing the overall understanding of the importance of treating
pain. The net result of these factors has been an increased use of strong opioids by non specialists
for the management of chronic moderate to severe pain.
The movement to treat chronic pain with strong opioids first gained acceptance in the treatment of
pain associated with cancer, for which concerns about addiction and abuse were believed to be
minimal.
Experience in treating chronic cancer-related pain suggested that other forms of severe,
chronic pain could be safely treated in the long term with opioid medications. As a result, opioids
have become a mainstay for reliably treating moderate to severe nociceptive pain, defined as a
physiologic response to neural inflammation produced by tissue damage from noxious stimuli.
Some specific sources include osteoarthritis, lower back injuries or conditions, and post surgical
trauma.9
Surgeons appreciate that a responsibility to manage pain is an integral part of their practice.
Multiple treatment modalities for optimally managing pain are frequently necessary, but
knowledgeable use of analgesic drugs is the most essential because drug therapy is the mainstay of
pain treatment. The most important analgesic drug group to understand is the opioids.
Opioids are potent, versatile, and safe (except for meperidine and propoxyphene, which
have toxic metabolites), but they are frequently underused in patients with chronic pain, such as
cancer patients, who are commonly seen in a surgical practice. Physicians are aware of the dangers
of opioid use, particularly respiratory depression, but many have complete understanding of the
safety of opioids, particularly with long term use. This leads to under prescribing and to inadequate
pain relief. The safety of opioids is related to two unique pharmacologic properties and to the
development of tolerance.10
Opiates by an action at specific receptors can induce a highly selective alteration in the
response of humans and animals to strong and otherwise aversive chemical, mechanical or thermal
stimuli. Specific investigations in a variety of species from rodent to primate using microinjection
techniques to examine the pharmacology of local drug action have shown potent antinociceptive
actions to be mediated by a receptor specific action at a number of sites within the brain, including
the periaquaductal gray (PAG: μ receptor), the rostral ventral medulla (μ/δ receptor) and the
substantia nigra (μ receptor) and within the spinal dorsal horn (μ/δ/K receptor).
Mechanistic studies have shown these actions in the different sites to be mediated by
several discrete mechanisms. For example, in the PAG, the local opiate effect is likely mediated by
the indirect activation of bulb spinal pathways, rostral projections to forebrain sites and by a local
alteration in afferent input into the brainstem core.
In the spinal cord, this effect is mediated by an action presynaptic to the primary afferent
and by a post-synaptic effect to hyperpolarize projection neurons. In addition, it is now appreciated
that μ and K receptors in the periphery can modulate the sensitized state of the small afferent
terminal innervating inflamed tissue and exert an anti-hyperalgesic action. After systemic delivery
of an opiate, it is thus clear that a wide array of central and peripheral systems serve to explain the
powerful analgesic effect exerted by this class of agents. 11
INTRODUCTION
1.1 Definition:-
The term “opioid” refers to a large group of compounds and chemicals that share the
characteristics of opium. Opium, from the Greek word “opos” for juice, refers to the liquid
collected from the unripe seed capsule of Papaver somniferum L., also known as opium poppy.
Opium has been used for medicinal purposes for centuries.1 Opioid analgesic are defined as "all of
the natural and semi synthetic alkaloid derivatives from opium, their pharmacologically similar
synthetic surrogates, as well as all other compounds whose opioid-like actions are blocked by the
nonselective opioid receptor antagonist Naloxone. Opioid analgesics, also called narcotics, are
drugs usually used for treating pain.
Opioid analgesics are prescribed for moderate to severe pain, particularly of visceral origin,
and are used in step two and step three of the analgesic ladder. Dependence and tolerance are well
known features with regular use although this should not inhibit prescribing in palliative care.
Some chronic non-malignant conditions benefit from analgesic control with opioids, but patients
should be reviewed regularly. One study showed that there has been a general increase in opioid
prescribing for a wide spectrum of non-cancer conditions. It may be appropriate to involve a
specialist in the decision to prescribe opioids long term for such conditions3.
In medicine, pain relieving agent that acts at receptor sites in the central nervous system.
Opiates are used to relieve moderate to severe pain. Drugs in this class include morphine,
Pethidine, and Diamorphine (heroin). Dependence and tolerance to these drugs can develop.4 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 effects of opioids
are due to decreased perception of pain, decreased reaction to pain as well as increased pain
tolerance Opioids can cause cough suppression, which can be both an indication for opioid
administration and 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
recreational use of opioids by many individuals.5
Opioids have played a critical role in achieving pain relief in both modern and ancient
medicine. Yet, their clinical use can be limited secondary to unwanted side effects such as
tolerance, dependence, reward, and behavioral changes.
Opioids are useful in a variety of chronically painful conditions (though they may have limited
effectiveness in some forms of neuropathic pain). For the purposes of chronic pain management,
only the oral and transdermal versions of various opioids will be considered in the following
discussion.
Pain is a crucial aspect of the body’s defense mechanisms
Pain “is a part of a rapid warning relay instruction the motor neurons of the central nervous
system to minimize detected physical harm.’’
Pain can be classified into two types
1.2.1 Acute Pain
Acute pain is short-term pain or pain with an easily identifiable cause.
Acute pain “is the body's warning of present damage to tissue or disease. It is often fast and
sharp followed by aching pain. Acute pain is centralized in one area before becoming
somewhat spread out. This type of pain responds well to medications.’’
1.2.2 Chronic Pain
Chronic pain is pain that last much longer than pain normally would with a particular injury.
Chronic pain can be constant or intermittent and is generally harder to treat than acute pain.
Pain can also be grouped by its source and related pain detecting neurons such as cutaneous pain,
somatic pain, visceral pain, and neuropathic pain Opioid Analgesics can be used to treat many
types of pain
1.2.3 What Causes Pain?
Pain is caused by the stimulation of pain receptors which are free nerve endings.
‘Nocireceptors are pain receptors that are located outside the spinal column in the
dorsal root ganglion and are named based upon their appearance at their sensory ends.’
These sensory endings look like the branches of small bushes. There are two types of
Nocireceptors that mediate fast or slow pain signals the perception of pain is when these receptors
are stimulated and they transmit signal to the central nervous system via sensory neurons in the
spinal cord.
Pain Signaling
These neurons release excitatory neurotransmitters which relay signals from one neuron to another.
The signals are sent to the thalamus, in which pain perception occurs. From the thalamus, the
signal travels to the somatosensory cortex in the cerebrum, at which point the individual becomes
fully aware of the pain.
1.3 What is Analgesia?
Analgesia simply means the absence of pain without loosing consciousness.
“The analgesia system is mediated by 3 major components : the periaquaductal grey matter
(in the midbrain), the nucleus raphe Magnus (in the medulla), and the pain inhibitory
neurons within the dorsal horns of the spinal cord, which act to inhibit pain-transmitting
neurons also located in the spinal dorsal horn..’’These areas are the areas in which the chemical
mechanisms of opioid analgesics will take place.7
1.3.1 Locations involved in Pain Signaling and Analgesia.
(1) Although the opioid (narcotic) analgesics such as morphine have proven very useful, serious
undesired effects often leads to under medication in clinical settings.
(2) The undesired effects associated with morphine include respiratory depression, tolerance,
constipation, dependence, and nausea.
Respiratory depressions the major cause of fatalities through illicit opioid use(generally with
diacetylmorphine or heroin.
(3), but such events can be generally controlled with therapeutic opiates through close observation
in a clinical setting.
The constipatory effects of morphine have been known for many years, and have proved
beneficial through its use as an anti-diarrhea agent. However, in a clinical setting, constipation
remains a major undesired effect, and the pain associated with constipation has been described as
often being worse than the pain the morphine is treating. Indeed, in extreme cases, the constipation
can be life-threatening
(4).These facts are the main reasons why chronic pain is often under medicated with morphine.
(5).Obviously, the development of novel analgesic medications lacking such deleterious effects
would prove extremely useful for physicians treating terminal cancer pain, and this manuscript will
discuss the potential approaches which can be taken by medicinal chemists in the design of agents
with a reduced profile of undesired effects. This manuscript does not attempt to present
comprehensive account of the known medicinal chemistry and pharmacology of opioids, but how
such knowledge could be applied to the discovery of new agents.8
1.4 OPIOID ANALGESIC IN PRIMARY HEALTH CARE:-
Chronic pain is a widespread and challenging problem for primary care physicians and
family physicians, particularly in patients with nonmalignant pain syndromes, who represent a
growing proportion of chronic pain diagnoses. For patients with moderate to severe acute or
chronic pain, nonopioid analgesics may not be sufficient to achieve adequate analgesia.
Historically, the use of opioids to manage pain has oscillated from broad indiscriminate use a
century ago to narrowly restricted use in subsequent decades that left too many people without
adequate analgesia. More recently, multiple forces have driven the increased use of strong opioids
in the management of pain, including an evolving regulatory outlook and increasing acceptance
from the clinical community. National legislation recognizing the importance of pain treatment has
been proposed, including an effort to establish a National Center for Pain and Palliative Care
Research.
The Agency for Health Care Policy and Research has established pain treatment guidelines,
and the Joint Commission on Accreditation of Healthcare Organizations has included pain
treatment in its evaluation of hospitals and healthcare providers. Reports on advances in pain
research in consumer media are increasing the overall understanding of the importance of treating
pain. The net result of these factors has been an increased use of strong opioids by non specialists
for the management of chronic moderate to severe pain.
The movement to treat chronic pain with strong opioids first gained acceptance in the treatment of
pain associated with cancer, for which concerns about addiction and abuse were believed to be
minimal.
Experience in treating chronic cancer-related pain suggested that other forms of severe,
chronic pain could be safely treated in the long term with opioid medications. As a result, opioids
have become a mainstay for reliably treating moderate to severe nociceptive pain, defined as a
physiologic response to neural inflammation produced by tissue damage from noxious stimuli.
Some specific sources include osteoarthritis, lower back injuries or conditions, and post surgical
trauma.9
Surgeons appreciate that a responsibility to manage pain is an integral part of their practice.
Multiple treatment modalities for optimally managing pain are frequently necessary, but
knowledgeable use of analgesic drugs is the most essential because drug therapy is the mainstay of
pain treatment. The most important analgesic drug group to understand is the opioids.
Opioids are potent, versatile, and safe (except for meperidine and propoxyphene, which
have toxic metabolites), but they are frequently underused in patients with chronic pain, such as
cancer patients, who are commonly seen in a surgical practice. Physicians are aware of the dangers
of opioid use, particularly respiratory depression, but many have complete understanding of the
safety of opioids, particularly with long term use. This leads to under prescribing and to inadequate
pain relief. The safety of opioids is related to two unique pharmacologic properties and to the
development of tolerance.10
Opiates by an action at specific receptors can induce a highly selective alteration in the
response of humans and animals to strong and otherwise aversive chemical, mechanical or thermal
stimuli. Specific investigations in a variety of species from rodent to primate using microinjection
techniques to examine the pharmacology of local drug action have shown potent antinociceptive
actions to be mediated by a receptor specific action at a number of sites within the brain, including
the periaquaductal gray (PAG: μ receptor), the rostral ventral medulla (μ/δ receptor) and the
substantia nigra (μ receptor) and within the spinal dorsal horn (μ/δ/K receptor).
Mechanistic studies have shown these actions in the different sites to be mediated by
several discrete mechanisms. For example, in the PAG, the local opiate effect is likely mediated by
the indirect activation of bulb spinal pathways, rostral projections to forebrain sites and by a local
alteration in afferent input into the brainstem core.
In the spinal cord, this effect is mediated by an action presynaptic to the primary afferent
and by a post-synaptic effect to hyperpolarize projection neurons. In addition, it is now appreciated
that μ and K receptors in the periphery can modulate the sensitized state of the small afferent
terminal innervating inflamed tissue and exert an anti-hyperalgesic action. After systemic delivery
of an opiate, it is thus clear that a wide array of central and peripheral systems serve to explain the
powerful analgesic effect exerted by this class of agents. 11
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