“Intro to the Treatment of Pain with Opioid Medications” by Dr. Charles Berde, for OPENPediatrics

“Intro to the Treatment of Pain with Opioid Medications” by Dr. Charles Berde, for OPENPediatrics

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Introduction to Treatment of Pain with Opioid
Medication, by Dr. Charles Berde. I’m Dr. Charles Berde, and I am Director of
the Division of Pain Medicine at Boston Children’s Hospital. Overview. In this lecture, we’re going to discuss some
general considerations regarding clinical approach to patients with pain, regarding
development of pain perception, and trade-offs with the use of analgesic medications. A first
point is that the experience of pain is protective. It helps us know which factors in the environment
may be helpful or harmful, and it helps us to shape learning and behavior. Treating pain
with analgesics always reflects a balance between benefits and potential risks, side
effects, or harm from analgesics. Pain transmission in the fetus develops steadily
through the second trimester. By full term, human infants show evidence of cortical activation
with noxious stimulation, and they show evidence of degrees of maturation of their pain responses,
though pain responses continue to mature during infancy. For human neonates and young infants
undergoing major surgery, pain evokes hormonal, metabolic, and autonomic stress responses.
And these stress responses can produce persistent patterns of vigilance and hyper reactivity. Analgesic medications work at a range of sites
in the periphery, in the spinal cord, and in the brain. Opioid analgesics work, in part,
by binding to opioid receptors, which are the targets of endogenous opioid peptides.
Opioid receptors are present in the periphery, especially in the gastrointestinal tract,
in the spinal cord, in the brain stem, and in forebrain areas that are involved in reward
and affective regulation. Examples of opioid analgesics that are commonly
used include– morphine, oxycodone, hydrocodone, hydromorphone, and methadone. Opioid analgesics
have very important roles for treating many types of pain. Some examples include pain
after surgery, pain after major injuries, and pain due to vaso-occlusive episodes with
sickle cell disease. They have crucial roles in treating pain due to advanced cancer, for
treating dyspnea in end-of-life care, and for permitting tolerance of mechanical ventilation
during critical illness. For each of these indications, opioids generally have a very
favorable balance of benefit versus harm. In other lectures in this series, you will
hear about some of the mechanisms that make pain become persistent or chronic. Chronic
pain is an extremely common problem in adults and is often associated with disability and
impaired quality of life. Some common types of chronic pain in adults include– mechanical
low back pain; neck pain; degenerative arthritis; widespread musculoskeletal pain, or fibromyalgia;
daily headache; irritable bowel syndrome; and pain due to nerve injury or nerve degeneration. Over the past 25 years, there has been a dramatic
increase in prescribing of opioids on a long-term basis for adults who have chronic pain due
to a non-life-limiting condition. Despite more than tenfold increase in annual prescribing
for these situations in the United States, there’s very little evidence that a majority
of people with these types of chronic pain due to non-life-limiting conditions, receive
a good balance of benefit versus harm when they are given opioids on a daily basis. For
most of these patients, in clinical trials, they do not show long-term reductions in pain
scores, and opioids do not seem to make them more active or more able to return to the
workplace. While individual patients do derive long-term
benefit from opioids, it is often hard to determine which those patients are and who
will benefit or who will not. Several factors regarding opioids should make us cautious
in considering long-term opioid prescribing. These include the development of tolerance,
opioid-induced hyperalgesia, which we’ll define subsequently, and some of the neuropsychological
and neuroendocrinal effects of opioids. Terminology. Several terms are widely used regarding opioid
actions. The definitions of these terms are important for understanding benefits and harms
of opioids. The term tolerance refers to a diminished effect, such as analgesia sedation
or respiratory depression, with repeated administration of the drug. Or it may mean a requirement
for an increased dose in order to get the same effect as was seen originally. The term
withdrawal refers to a set of symptoms and physical signs that occur when opioid administration
is suddenly stopped or is tapered rapidly in a subject who has opioid tolerance. The term dependence means the capacity to
experience withdrawal when opioids are tapered or when an opioid reversal agent is given.
The term addiction should be distinguished from either tolerance, withdrawal, or dependence.
Addiction properly refers to a condition of compulsive drug seeking. Tolerance, withdrawal, and dependence may
coexist with addiction, but they need not. For example, a patient receiving opioids for
advanced cancer or during intensive care may become tolerant and dependent and they may
be experience withdrawal if dosing is tapered too rapidly. But these subjects may never
develop craving or euphoria or drug seeking or any of the other features that are common
for addiction. Along with tolerance and dependence, another feature that may occur with prolonged
opioid administration is a resetting of pain responsiveness. The term for this resetting
is opioid-induced hyperalgesia. Opioid-induced hyperalgesia refers to a situation
in which subjects appear to experience new forms of pain more acutely and with a lower
threshold than at baseline. It is not clear what factors make this happen, for some people
more than others, or how common it is, but opioid-induced hyperalgesia should be considered
in those situations when patients show hypersensitivity to new forms of pain, as well as reduced responsiveness
to analgesics. A number of non-opioid pain medications may help to reduce or to reverse
opioid-induced hyperalgesia and they may be considered in these situations. Opioid Properties. In general, infants and children with cancer,
with sickle cell disease, or with major surgery respond to opioid analgesics with good pain
relief, and with a good margin of safety. Infants may have an increased susceptibility
to hypoventilation due to opioids. And those infants that are naive to opioids– meaning,
those who have not been prescribed them previously– should have particular attention to titrated
dosing and observation, to prevent episodes of hypoventilation. Hospitals caring for children need to develop
protocols that take into consideration the particular concerns around opioid prescribing
and monitoring for young infants, and for infants and children who have diseases that
may increase these risks. Many disease states can influence how opioid
analgesics act. These influences can be pharmacokinetic, which means they have an influence on how
drugs are metabolized and eliminated. Or these disease states may influence how opioids act
on their targets; meaning pharmacodynamic influences. For example, liver disease can affect the
metabolic inactivation of many opioids. But this effect may be particularly pronounced
for opioids such as methadone or fentanil. Similarly, some opioids are converted in the
liver to active products that may have analgesic sedative respiratory depressant, or excitatory
actions. These active products are then excreted by the kidneys. In these situations, these active products
can accumulate in patients with renal insufficiency. For example, morphine’s actions are greatly
exaggerated in the presence of renal insufficiency, due to accumulation of morphine’s metabolic
products, namely, morphine-3-glucuronide and morphine-6-glucuronide. Infants in the first 3-6 months of life have
immature hepatic enzyme systems, and reduced glomerular filtration rates. And part of the
susceptibility of young infants to opioids is based on immaturity of drug metabolism
and elimination. A number of gene variants influence drug metabolism.
And these variants can be particularly important for opioids such as codeine. Codeine is an unusual opioid, in that it is
really a prodrug. This means that it only works by metabolic conversion to morphine
as the active drug. Codeine without metabolic conversion is largely inert. Overall, codeine is a weak analgesic. And
it’s often even more ineffective in patients with some common metabolic patterns. Gene
variants that give rise to slow conversion of codeine to morphine result in even less
effective analgesia than the more common genotypes. Of even greater concern, there are gene variants
that lead to ultra rapid conversion of codeine to morphine. In people with these ultra rapid
conversion variants, codeine has produced overdose and deaths in patients sent home. For these reasons, we– and the FDA– recommend
substituting other opioids instead of codeine, as a general change in pediatric practice. Pharmacodynamic susceptibility refers to changing
responsiveness to opioids at their sites of action, rather than changes due to drug metabolism
or excretion. For example, children with obstructive sleep apnea or sleep disordered breathing
show greater risk of hypoventilation for morphine and other opioids, and they require smaller
doses of morphine and other opioids in order to achieve analgesia. Increasingly we’re recognizing genetic variants
that either increase or decrease pharmacodynamic susceptibility to opioids. For example, there
are mutations that affect the opioid receptor, per se, that change susceptibility. It is likely that in the future, screening
for these variants, and providing clinical decision support around how to adjust dosing,
will become inexpensive and rapid. And hopefully we’ll have good positive and negative predictive
value, and thereby become a routine part of improving our practice. Opioid Prescribing. Earlier in the lecture, I discussed the controversy
regarding chronic prescribing of opioids to adults who have chronic pain due to non-life-limiting
conditions. These controversies and these concerns may be even more acute for children
with chronic pain. There are concerns regarding longer term effects
of opioids on cognitive development, endocrine development, and mood regulation. In addition,
adolescence is a time of increased susceptibility to many types of addictions, including addiction
to opioids. The time course of tolerance to opioids also
appears age-dependent. Younger subjects get tolerant more rapidly than older subjects.
All of these issues suggest that pediatricians and pediatric subspecialists should be very
careful in choosing a course of long-term opioid prescribing for a child who has chronic
pain due to a non-life-limiting condition. While chronic opioid prescribing is appropriate
for some children, it requires careful patient selection, ongoing monitoring, considering
of alternative methods of pain relief, and weighing of risks and benefits. We recommend having a thoughtful, informed
consent discussion with patients and parents, and an informed consent agreement, prior to
consideration of long-term opioid prescribing not associated with end-of-life conditions. When prescribing opioids for acute pain, it
is worth knowing the usual recommended starting doses. But it is important to recognize that
many patients require higher or lower doses, and that doses need to be adjusted based on
clinical response. In this sense, the right dose of morphine is different from the right
dose of amoxicillin, for example. Consider three scenarios involving children
receiving morphine, 0.1 milligram per kilogram, intravenously, as a first dose of medication
following coming to the emergency department for a femur fracture. For our first child, this dose of 0.1 milligrams
per kilo might produce good pain relief, a modest reduction in respiratory rate– from
an initial tachypnea down to a normal range– and minimal sedation. And you might conclude
that this is a reasonable and appropriate dose. Consider a second child. For the second child,
this dose might produce minimal pain relief, no reduction in their rapid respiratory rate
or heart rate, and you would conclude that additional incremental dosing is needed to
get pain relief. For a third child, that initial dose of 0.1
milligram per kilo might produce very good pain relief, but slowing of respiration and
considerable sedation. For this third child, you would observe closely, wait until over-sedation
and relative hypoventilation improve, and you would conclude that subsequent morphine
doses should be substantially reduced. For example, you might decide that after the
sedation resolves, that the next morphine dose would be 50% of the previous dose. Pain Assessment. In clinical practice, pain assessment involves
a combination of self-report, behavioral assessment, and physiologic assessments. Self-report means
asking patients to rate the location, intensity, and quality of pain. In a setting of persistent
pain, it is important to ask patients how they’re pain impacts on daily functioning
and quality of life. In adults, it is very common to rate pain
intensity using visual analog or numerical rating scales that ask the patient to rate
their pain on a scale of 0 to 10, where 0 is no pain and 10 is worst possible pain.
These scales have reasonable psychometric properties for adults with acute pain and
for pain due to cancer. And they have good clinical utility for most typically developing
children and adolescents from about the age of 8 and older. For children ages 4-8, there were a number
of self-report tools based on presenting the child with a series of faces and asking them
to rate which one is like how they feel. And there are scales with a slide rule, where
increasing red color means more intense pain. And the child is asked to move the slide until
it’s a color intensity that simulates their pain. Behavioral assessment involves a range of
observation including facial expression, posture, movement, mental clarity, and level of sedation
or arousal. Behavioral assessments are particularly important for neonates, for infants and pre-verbal
children, for patients with developmental and communication difficulties, and during
intensive care. Some pain behaviors can be surprising at first
glance. For example, neonates experiencing ongoing post-operative pain may close their
eyes tightly, furrow their brow, grimace, clench their fists, but not necessarily cry.
If you just look at a baby with closed eyes who’s not crying, you might mistakenly concluded
that baby is comfortable or sleeping. It’s common in this setting to see that after
giving additional doses of an opioid, such as morphine, that the baby’s facial muscles
and fists relax, and the baby’s eyes open, and he or she begins to look around more. A commonly used behavioral scale is called
the FLACC. This consists of five items, namely facial expression, leg posture, activity,
crying, and consolability. For each item, it is scored from 0 to 2, so that the composite
score can range from 0 to 10. So in this setting, withdrawal from the environment may be the
response to pain, rather than active movement or crying or flailing. Sometimes behavioral assessments can overrate
pain or underrate pain relative to patient self-report. For example, consider a 3-year-old
having an ear exam. This exam is not painful, but it’s scary. And a scale that rates screaming
and crying and bodily movements may falsely rate distress that is due to fear and anxiety
rather than due to pain. Conversely, in the setting of ongoing persistent
pain, some younger children react by withdrawal and inhibition of movement and lying still
because it hurts too much to move. Behavioral scales that were developed issue initially
for acute pain and procedural pain may underrate persistent pain in these children. In the setting of persistent pain, it’s also
important to observe how the patient functions in self-care, in attendance and participation
in school or work. And it’s important to assess where there appears to be a discrepancy between
their reports of pain and how they behave. When there are apparent discrepancies between
self-report and behavior, clinicians should consider some possible reasons for these discrepancies.
But we should be cautious and open-minded in our interpretation. In general, interpretations
regarding psychological factors in persistent pain should be based on positive identification
of such factors, not simply on our difficulty in finding a physical explanation for the
pain. Physiologic assessments include recording
of heart rate, blood pressure, respiratory rate, and pupilary diameter. Relative changes
in these parameters are often useful for gauging pain relief. For example, in titrating opioid
analgesics, a change in respiratory rate and depth and reduction in heart rate are often
useful indicators of analgesic effect. It is highly recommended that health care
facilities caring for infants and children adopt uniform standards for pain assessment
and recording. And that these assessments form one part of a more global approach to
rating effectiveness of pain treatment. Please help us improve the content by providing
us with some feedback.

3 thoughts on ““Intro to the Treatment of Pain with Opioid Medications” by Dr. Charles Berde, for OPENPediatrics”

  1. Ty for explaining this intelligently, but up here in the state of Maine I am suffering. Tried every non opioid pain med I can find. Have RRMS and am about to destroy my liver with nsaids. Went from thinking I can going back to work to a bed to couch life.☹️ please FDA help chronic pain sufferers. Not drug addicts whom apparently are the only people helped in my state of Maine.

  2. Great video! You explained it very clearly!
    I just started my own medical youtube channel, and I also made a video on Morphine.
    However I still find it hard to find the balance between informational content and a fun way to explain it.
    You do this in a very natural way, which inspired me to make my videos more visual.
    Keep it up!

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