| Opioid Agonist | IM/IV/SQ | Oral | Conversion Factor | Half Life | Starting Dose |
| Morphine | 10 | 30 | 3 | 2-3 hours | 5 mg IV Q 4 |
| Controlled Release Morphine (MS Contin) | - | 30 | - | 15 mg PO Q12 | |
| Codeine | 130 | 200 NR | 1.5 | ||
| Hydromorphone (Dilaudid) | 1.5 | 7.5 | 5 | 1 mg IV Q4 | |
| Levorphanol (Levo-Dromoran) | 2 | 4 | 2 | ||
| Methadone (Dolophine) | 10 | 20 | 2 | ||
| Meperidine (Demerol) | 75 | 300 NR | 4 | Don't | |
| Hydrocodone (Lorcet, Lortab,Vicodin, others) | N/A | 30 | N/A | 10 mg PO Q3-4 | |
| Oxymorphone (Numorphan) | 1 | (10 rectal) | N/A | ||
| Fentanyl | 100ug/hr | N/A | N/A | ||
| Fentanyl Patch | 0.1 | - | 25 mcg/hr=50 mg Morphine PO Q24hrs | ||
| Controlled Release Oxycodone (Oxycontin) | - | 20 | - | 10 mg PO Q12 | |
| Oxycodone (Percocet, Tylox) | N/A | 20 | N/A | 5 mg PO Q4 | |
| Propoxyphene | -- | ?NR | N/A | ||
| Methadone | 1-10 | 2-20 | |||
no difference in pain control between hydrocodone 5 mg and oxycodone 5 mg (Acad Emerg Med 2005;12(4):282)
0.015 mg/kg of dilaudad was equivalent to 0.1 mg/kg
Oral Morphine per day/2 = fentanyl patch per hour
Give 10% of 24 hour dose for breakthrough
Give everyone colace (softens), senna 2 tabs Qhs (stimulant), lactulose (large sugar)
IV opioids take 8 minutes, Oral 60-120 minutes, SC 20-30 minutes
Increasing dose, mild to moderate 25-50%
Severe 50-100%
Rescue dose 20%
works at the μ receptors
90% metab by liver conjugation
contains Sodium Bisulfate which may cause allergic reactions
histamine release may cause appearance of reactions
Dilaudad
Toradol-no advantage over
Fentanyl
Nubain
Ultram
Just b/c one opioid doesn't work does not mean another one in same class will not, start at 50% of prior dose with new med.
Chronic pain actually forms neuronal connections between somatic and pain sensory fibers causing pain with normal sensations= allodynia . Can also cause mood changes, depression, insomnia
12 hrs for fentanyl patch to work. warm temp allows more in, cold less.
Oxycontin gives a surge dose then the rest is time released.
Methadone's analgesia lasts 6 hours.
Do not use NSAIDS unless no worry at all for GI Bleed
Instead use Bextra, as effective as Vioxx but without the side effects. Only worry in patients with renal failure (Audio Digest Chronic Pain) Can give 20 mg BID for 5 days and then 10 mg BID.
The answer, it
would seem, lies in the fact that there is highly variable expression in the
brain of the gene to produce cytochrome P450 2D6 55. There appears to be
moderate ethnic variability, with the most ‘non-converters’ being in whites. In
this group, up to 10% are non-converters and up to another 10% are poor
metabolizers 56. With Asians, only 1% are non-converters.
This means to me that current studies suffer from the fact that there has not
been an effort to look at how well this drug works in known converters. Taking
the population as a whole, up to 20% can be expected to have diminished or no
analgesic effects. Eliminating 1 in 5 people would significantly skew the
results.
I am still awaiting a study on codeine that takes this into account. I may still
be convinced that it is a poor drug. Until then, I think it makes sense to NOT
prescribe codeine as an unknown – i.e. for someone new to narcotic pain relief.
This both because of the studies such as mentioned and because there is a finite
chance (10-20%) the patient will be a non-converter.
On the other hand, it is probably medical myth to assume it never works. With
the occasional patient that requests it, and has felt it worked in the past, it
is reasonable to use. (RaneyFacts)
5% expressed poorly
5% not expressed at all
p450 enzyme needed to metab codeine to morphine
These studies also suggest that the analgesic
effect of codeine is either wholly
or mostly dependent on its metabolism to morphine.6
7 Metabolism of
codeine to morphine is catalysed by the
cytochrome P450 enzyme
CYP2D6. Over 50 different genetic variants are known to exist for
CYP2D6, which leads to a wide spectrum of metabolic capabilities
within populations.8
9 Individuals are normally classified
as either poor metabolizers (PM) or extensive metabolizers (EM),
depending on the activity of the enzyme,
although this is known to be an oversimplification. PMs will produce
little or no morphine from codeine
whereas EMs will produce morphine, although the actual amount may
show wide variation.10–12
Robaxin Take 1500 mg Q2hrs as long as no cognitive deficits as loading dose, then switch to the 1000 mg-1500mg QID. Do not use generic, it is not as good. If there is an inflammatory process, you need NSAIDs as well.
Use gabapentin for all of neuropathic pain. Worry about it only in renal patients. it does not affect drug levels.
Use Ultram instead of opioids for acute and chronic pain
Actin is the Fentanyl citrate lollipop Works very rapidly
Demerol's metabolite normperidine causes seizures and highs.
Myofascial pain: true trigger points cause pain elsewhere when pressed. Travel lists the triggers.
Reflex Sympathetic Dystrophy (RSD): calcitonin 200 IU IN OD, it takes a few days to work
Fentanyl Infusion at 2/3 bolus dose/hour
Analgesic adjuvants to opioids
• Anesthesiology 1999: 0.5 mg/kg ketamine
PO q12h
– Decreased need for breakthrough oral opioids,
less somnolence
• J Pain and Symptom Management 1999
– 0.1 – 0.2 mg/kg/hr infusion ketamine in
terminal patients relieved pain morphine could
not
Acute Pain Management in Trauma
Give fentanyl bolus until relief then start drip at 2/3 required dose per hour
Patient activated transdermal patches as good as IV PCA (JAMA 3/16/04)
normeperedine can last up to 40 hrs in the elderly
--------------------------------------------------------------------------------
Ketamine for Perioperative Pain Management (Anesthesiology Volume 102(1) January
2005 pp 211-220)
Neuropathic Pain
Use opioid and gabapentin in combination ( NEJM Volume 352:1324-1334 March 31, 2005 Number 13)
Use ketamine for the RSI and then keep it going for pain control
0.1 mg/kg infusion
Topical anesthesia for all ng tubes
5 cc of lidocaine jelly 5 minutes before procedure
Intradermal lidocaine for IV starts
It is PROCEDURAL SEDATION, not conscious sedation
Titrate analgesia and then sedation
Even if you use incredibly potent sedative, patients still need pain control because pain is a spinal reflex and patients will have greater post-procedural pain. Pain is inducible
Best way to break spasm, like in lower back pain, is to stop the pain. Just keep titrating the opioids until pain is stopped. Then they must be treated with lower doses for 24-36 hours
NSAIDS require induction of Cox-2 receptors and give no relief in the first few hours
Canabinoid Canabinoid receptors receptors
CB1 receptor stimulation produces receptor stimulation produces
two effects:
Analgesia
Addictive behavior
NOT endorphin sites that lead to addiction, only dependence
Methylnaltrexone Methylnaltrexone (MNTX) (MNTX)
n No central antagonism No central antagonism – does not cross BBB does not cross BBB
n Well absorbed PO Well absorbed PO
n Alvimopan Alvimopan
n Mu Mu selective antagonist selective antagonist
n Minimal intestinal absorption Minimal intestinal absorption Bates 2004
Alvimopan Alvimopan 6 mg bid PO 6 mg bid PO
n Shorter bowel recovery time, 1 day earlier discharge
Alvimopan Alvimopan 6 mg pre 6 mg pre-op decreased post op decreased post-op op
N&V from 23% to NONE N&V from 23% to NONE
Taguchi 2001
NSAIDs NSAIDs
n Can act as analgesic only if Can act as analgesic only if arachadonic arachadonic acid / acid /
prostaglandin cascade activated prostaglandin cascade activated
n Not effective in neuropathic pain Not effective in neuropathic pain – no tissue injury no tissue injury
or inflammation or inflammation
n Osteoarthritis good example of no inflammation, Osteoarthritis good example of no inflammation,
little effect little effect
n Requires 4 Requires 4-6 hours for blood 6 hours for blood-borne mediators to borne mediators to
induce COX induce COX-2 receptors in dorsal horn 2 receptors in dorsal horn – cannot cannot
obtain relief from obtain relief from NSAIDs NSAIDs in first few hours.
Renal colic in majority of cases caused by raised
intra intra-mural tension mural tension
n NSAID will decrease that tension, requires 15 NSAID will decrease that tension, requires 15-20 20
minutes minutes
n NOT effective in 15 NOT effective in 15-30% of patients as pain induced 30% of patients as pain induced
by other mechanisms by other mechanisms
n Note that pain control due to direct impact on mural Note that pain control due to direct impact on mural
stretch receptors, so does not require COX stretch receptors, so does not require COX-2
induction induction
ACUTE PAIN MANAGEMENT IN THE EMERGENCY
DEPARTMENT
James Ducharme MD CM, FRCP
Dalhousie University, Department of Emergency Medicine
Saint John Regional Hospital
Reference List
· Johnston CC, Gagnon AJ, Fullerton L, Common C, Ladores, Forlini S. One-week
survey of pain intensity on admission to and discharge from the emergency
department: a pilot study. Journal of Emergency Medicine 1998; 16(3):377-382.
· Unruh AM, Ritchie J, Merskey H. Does gender affect appraisal of pain and pain
coping strategies? Clinical Journal of Pain 1999; 15(1):31-40.
· Raftery KA, Smith-Coggins R, Chen AHM. Gender-associated differences in
Emergency Department pain management. Ann Emerg Med 1995; 26:414-421.
· Kelly AM. Does the clinically significant difference in visual analog scale pain
scores vary with gender, age, or cause of pain? Academic Emergency Medicine
1998; 5(11):1086-1090.
· Horgas AL, Tsai PF. Analgesic drug prescription and use in cognitively impaired
nursing home residents. Nursing Research 1998; 47(4):235-242.
· Acute pain management guideline panel. Acute pain management: Operative or
medical procedures and trauma, Clinical Practice Guidleine No 1. Publication No.
920032. 1992. Rockville, Md, U.S. Department of Health and Human Services,
Public Health Service, Agency for Health Care Policy and Research.
Ref Type: Report
· Singer AJ, Richman PB, Kowalska A, Thode HC, Jr. Comparison of patient and
practitioner assessments of pain from commonly performed emergency
department procedures. Annals of Emergency Medicine 1999; 33(6):652-658.
· Todd KH, Funk JP. The minimum clinically important difference in physicianassigned
visual analog pain scores. Academic Emergency Medicine 1996;
3(2):142-146.
· Ducharme J, Beveridge RC, Lee JS, Beaulieu S. Emergency management of
migraine: is the headache really over? Academic Emergency Medicine 1998;
5(9):899-905.
PAIN: OF COURSE IT’S ALL IN YOUR HEAD
NEUROBIOLOGY OF PAIN
DEFINITION
IASP: "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Even the authors were aware of this definition’s inadequacy, and hastened to add: "Pain is always subjective… This definition avoids tying pain to the stimulus".
Despite the disclaimer, this definition DOES tie the sensation to the stimulus, perpetuating the centuries old fallacy. It does not, and cannot, explain many of the perplexing aspects of pain experience, and it does not consider the crucial influence of the brain on the sensation and the perception of pain.
THE PUZZLE OF PAIN
Without the contributions of modern neuroscience, it is impossible to unravel the multitude of the pain puzzles:
NOCICEPTION AND PAIN PATHWAYS
Stimuli from the periphery (mechanical, chemical, thermal) are transmitted to the spinal cord through the sensory afferent nerves.
Damaged tissue is a source of many amines and peptides that stimulate sensory nerve endings: bradykinin, adrenaline, 5HT, PGE2, IL-1, IL-6, TNF-alpha, etc.
These afferents synapse on the dorsal horn second order neurons in the spinal column (projection neurons), which form pathways extending to the brain – primarily thalamus and somato-sensory cortex.
Acute, physiological pain is mediated in the spinal synapses mainly by the GLUTAMATE-activated AMPA type of glutamate receptors.
In addition to glutamate, excitatory transmitters include AcCh, substance P, and CGRP, while GABA, enkephalin, 5HT and NA provide the inhibitory neurotransmission.
NEUROBIOLOGY OF CHRONIC PAIN
Chronic pain is not just a prolonged acute pain; it is a distinct entity, with many functional and structural alterations of the peripheral and central nervous system.
ERIPHERAL SENSITIZATION – PRIMARY HYPERALGESIA
Peripheral nociceptive hyperexcitability is induced through increased receptor (autosensitization) or cell membrane (heterosensitization) reactivity to stimuli, usually sustained presence of inflammatory factors.
CENTRAL SENSITIZATION – SECONDARY HYPERALGESIA
Central hyperexcitability is the key process in the generation of chronic pain. It is mediated by NMDA-type of post-synaptic glutamate receptors, and it results in transcriptional changes and manufacturing of the c-fos protein (the marker of central sensitization) in the second order dorsal horn projection neurons.
Repetitious and intense activation of the high-threshold C-fibers and AMPA post-synaptic receptors results in activation of the NMDA post-synaptic receptors (through dislodging the Mg ions and opening the N and Ca channels to Ca influx) and the NMDA mediated WIND-UP phenomenon (augmented response of the dorsal horn neurons to the same intensity stimuli).
Activation of the NMDA-receptors represents the first step in central sensitization, i.e., the transition from acute to chronic pain.
Knowing this makes it easy to realize that adequate treatment of physiological, nociceptive pain is the most important goal of acute pain management – prevention of central sensitization!
Other changes involved in central sensitization include substance P – NO (nitric oxide) cascade (with expansion of the receptive fields), increased release of NPY, VIP, galanin, and somatostatin from the pre-synaptic C-fiber terminals, hyper-sensitization of the WDR (wide dynamic range) neurons to non-nociceptive stimuli, expression of substance P by A-fiber pre-synaptic terminals, and sprouting of A-fiber terminals into the superficial layers of the dorsal horn (thus synapsing onto the nociceptive second order neurons).
Reorganization or remodelling of the synapses at the dorsal horn level, as well as at the brainstem, thalamus, and somatosensory cortex levels, is a well-documented phenomenon, referred to as neuronal plasticity, responsible for a variety of chronic pain syndromes.
Central sensitization and neuroplastic remodeling are responsible for all the main features of chronic pain: hypersensitivity to nociceptive stimuli (hyperalgesia), perception of pain upon non-nociceptive stimulation (NNP and allodynia), expansion of the pain-receptive fields and trigger-zones, and delayed pain.
Changes in central sensitization can be viewed as:
Activation of the NMDA- receptors, wind-up, sensitization of WDR neurons, expression of substance P by A-fibers
Dying-off of C-fiber terminals, sprouting of A-fiber terminals, extensive reorganization of the somatosensory cortical maps, remodeling in the brainstem, cerebellum, basal ganglia, and motor cortical areas.
DYSFUNCTIONAL DESCENDING INHIBITION – FAILURE OF INTERNAL ANTINOCICEPTION
As illustrated in PAIN PATHWAYS, nociception activates not only the afferent pathways, but also a variety of segmental and descending, inhibitory or anti-nociceptive pathways (SLIDE 5). Increased brainstem CCK, and deficiencies in the descending enkephalin, 5HT, and NA pathways, can all contribute to dysfunctional anti-nociception.
Processing of pain at the brain level has profound implications for both, the perception of pain, and for the management of pain.
Ascending pain pathways are relayed through the thalamus to the somatosensory cortex, which is responsible for the initial localization and the intensity of the stimulus (SENSORY-DISCRIMINATIVE function), as well as to the limbic brain structures, esp. the anterior cingulated cortex, which is responsible for the unpleasant, aversive aspect of the experience (AFFECTIVE-MOTIVATIONAL function). Both of these areas communicate extensively and reciprocally with the prefrontal cortex, which brings the situational and memory context to the experience (COGNITIVE-EVALUATIVE function).
These three aspects of pain experience (R. Melzack’s gate and neuromatrix theory of pain) make a variety of pain treatment modalities potentially helpful, and at the same time provide the neurophysiological and neurostructural explanation of these modalities’ efficacy (dismissing, in the process, all kinds of hogwash that has been written about "psychogenesis" of pain).
CHRONIC PAIN SYNDROMES
Chronic pain is generally categorized, according to etiological factors, as stemming from tissue damage – inflammatory pain, or from
nerve damage – neuropathic pain. The former is evident in various injuries (low back pain), infections, inflammatory diseases (RA, IBD, SLE) and immune/neuroendocrine dysfunctions (possibly FM/CFS, MPS). The latter is encountered in diabetes, certain infections (shingles), cancer, traumatic nerve injury, and following amputations (limb, breast).
Opioids are exceedingly effective in managing inflammatory pain, whereas they are less effective in managing neuropathic pain, due to the loss of pre-synaptic opioid receptors, and the extensive re-wiring of the dorsal horn synaptic circuits.
Low back pain
In up to 85% of sufferers, there is no detectable damage ("no objectively demonstrable organic pathology"); in only about 15% can one of the five recognizable causes (herniated disc, arthritis, infection, tumor or fracture) be demonstrated.
In addition, it is estimated that about 10% of low back pains develop a neuropathic dimension, making the picture even more puzzling. The vast majority of chronic low back pain sufferers continue to be under-treated or maltreated, labeled as "somatizers" or malingerers, despite ample evidence for central sensitization and somatosensory mapping reorganization in such patients.
Fibromyalgia and Myofascial Pain Syndrome
There is ample evidence in these disorders, as well, of altered central processing of the incoming nociceptive and non-nociceptive stimuli, at both the spinal and the brain level. Incoming stimuli from muscle C-fiber afferents are much more potent inducers of central sensitization than skin afferents, explaining lower pain threshold (hyperalgesia) and pain on movement (proprioceptive allodynia) in these patients. In addition, a dysregulated neuroendocrine stress response (decreased cortisol, growth hormone and IGF-1 secretion) may compound the picture in about a third of patients.
Phantom limb pain
Phantom pains affect over 70% of amputees, and persist for 2-7 years in about 60% of them; fewer than 15% obtain total pain relief. Extensive somatosensory cortex reorganization, with expansion of the trigger zones, has been demonstrated in numerous brain imaging studies.
Peripheral ectopic discharges (from the stump neuroma), deafferentation hyperexcitability, and unmasking of the underlying silent connections, may all be contributory.
In addition to phantom limb pain, phantom pains following mastectomy, and phantom body pains below the spinal cord section in paraplegics, are gaining increasing recognition.
DIAGNOSIS OF CHRONIC PAIN: CARTESIAN DUALISM, PSYCHOBABBLE AND ARROGANT IGNORANCE
Clinical features of chronic pain can be confusing and difficult to comprehend for the examining physician, leading to the characterization of the patient’s complaints as "non-organic", "psychogenic", "hysterical", "somatizing", and "hypochondriacal", or as evidence of "illness/pain behavior", "emotional overlay", or even malingering.
Especially puzzling is:
These features (we now recognize them as classical features of non-nociceptive pain) not only lead to the diagnosis of psychopathology (psychiatric or "functional" illness), but, more importantly, create a poisonous atmosphere in which the patient is blamed for "needing or creating" his pain, and is deprived of the necessary and effective treatment.
Thus, it is imperative to keep in mind that medically unexplained pain - pain with non-anatomical characteristics, or incongruent with observable pathology, is NOT evidence of psychopathology. Frequently, the presence of psychological distress, and the elevated hysteria, hypochondriasis, and depression scales on the MMPI, which are the consequences of pain, are cited as the cause of pain (despite evidence that they normalize with improvement in pain). As well, both the success and failure of psychological treatment are attributed to psychological factors and "illness behavior".
Meanwhile, the challenge should remain for the modern-day Cartesian dualists to provide the empirical evidence and proof that psychopathology causes pain, and, in so doing, to specify the mechanisms by which it does!
It is becoming increasingly apparent that the domain of the psychiatric "somatization" diagnosis is shrinking, as neuroscience keeps expanding our knowledge of NNP (non-nociceptive pain) mechanisms.
We, as physicians, should heed the exhortations of the medical masters, past and present:
"Pain must be regarded as a disease… and the physician’s first duty is action – heroic action – to fight disease". (Benjamin Rush)
"Few things a doctor does are more important than relieving pain… pain is soul destroying. No patient should have to endure intense pain unnecessarily. The quality of mercy is essential to the practice of medicine; here, of all places, it should not be strained". (Marcia Angell)
TREATMENT OF CHRONIC PAIN
DRUGS
Historically, two herbs have provided humanity with pain relief: willow and poppy. Even today, 95% of the analgesics in use are derivatives of either ASA or opium.
ASA and NSAIDS are usually the first line approach to the treatment of chronic pain, esp. pain of inflammatory variety. When combined with opioids, they may have a synergistic effect.
ANTIDEPRESSANTS have been used with varying degrees of success. The most commonly used ones are amitriptyline and trazodone, since they also enhance SWS (slow-wave sleep, i.e., stage III and IV of sleep), a feature of particular advantage in treating fibromyalgia (cyproheptadine and zolpidem may be useful in this regard, too). Many other antidepressants have been used, including, more recently, the dopaminergic ones. Bupropion has been found useful in some cases of neuropathic pain.
ANTICONVULSANTS gabapentin and lamotrigine are generally used as the first line approach to the neuropathic pain.
GABA agonists are also of considerable value; baclofen – a GABAB agonist – is particularly useful in treatment of spastic pains.
AMPHETAMINES have been used in combination with opioids for treatment of severe, intractable pain.
ALPHA-2 AGONISTS – clonidine – are sometimes extremely effective and highly synergistic when combined with opioids.
SUBSTANCE P ANTAGONISTS have shown a potent analgesic effect in clinical trials, and at least one preparation should be available for general use soon. Interestingly, this same agent has been quite effective as an antidepressant, as well.
CCK ANTAGONISTS – proglumide 200-250 mg p.o. – cancel CCK antagonism to opioids, augments opioid analgesia, and restores opioid effectiveness in neuropathic pain.
NMDA-RECEPTOR ANTAGONISTS
Recognition of NMDA-receptors as mediators of chronic pain has opened up a huge area of research. Drugs that block these receptors have a glorious potential in the treatment of chronic pain, esp. the neuropathic pain. When combined with opioids, they have a synergistic effect, and can restore opioid sensitivity in neuropathic pain.
The currently available agents in N.America are ketamine (I.V. – 0.3mg/kg x 10 min.: substantial reduction in FM pain lasting 7 days), dextromethorphan (10-30 mg/kg B.I.D.), and amantadine, but two very promising agents in wide usage in Europe – flupirtine and memantine – should become available soon. Research on ziconotide – a snail venom derivative – looks extremely promising.
OPIOIDS
The most effective by far, and the most feared and underutilized drugs in the treatment of chronic pain are the opioid analgesics. Prejudice, paranoia and ignorance surrounding these drugs, are the main reasons behind the inadequate treatment of chronic pain and a colossal amount of unnecessary suffering that it causes.
The main effects of opioids (both external and internal) are achieved through stimulation of the mu-opioid receptors. They amount to 70% of the spinal opioid receptors, while the share of delta and kappa receptors is about 25% and 5%, respectively.
The vast majority of opioid receptors in the dorsal horn – about 70% of the total mu-receptors – are located on the pre-synaptic terminals, where they potently inhibit the release of glutamate and substance P from the C-fiber afferents. Post-synaptically, they cause membrane hyperpolarization (preventing the NMDA-receptor activation and the wind-up phenomenon), while also stimulating the inhibitory GABA interneurons.
The loss of pre-synaptic mu-receptors in injured or severed nerves, explains the reduced effectiveness of opioids in neuropathic pain.
Opioid analgesia is usually initiated with the short half-life agents, given q 3-4 h:
Morphine 15-30 mg
Codeine 30-60 mg
Oxycodone 10-15 mg
Hydrocodone 10-15 mg
Hydromorphone 2-4 mg
Caution: CYP 2D6 inhibition reduces the effectiveness of codeine, oxycodone and hydrocodone (preventing formation of active metabolites).
Once the effective drug is found (44% of patients required trials of 2 or more, while 20% required trials of 3 or more opioids), a sustained-release opioid is substituted, in the same daily dosage, given b.i.d. or even o.d.
The 24-hour baseline dose, for sustained release opioids, is:
Morphine 60 mg
Codeine 200 mg
Oxycodone 30 mg
Hydrocodone 40 mg
Hydromorphone 7.5 mg
Methadone 20 mg
Levorphanol 4 mg
Fentanyl 25 microg transdermal patch, lasting 72 hours: equivalent to 45-135 mg/day of oral morphine; doesn’t pass through the liver, less constipation.
Oxycodone is the most utilized sustained-release opioid, due to fewer side-effects, easy titration and marked effectiveness in visceral pain (probably by added stimulation of kappa-receptors).
Methadone and levorphanol are opioids with NMDA-antagonist effects, but are difficult to titrate, and exhibit delayed-onset side-effects, esp. sedation.
Every patient on sustained-release agents should be provided with RESCUE MEDICATION – a fast-acting opioid to treat BREAK-THROUGH pain; this may be needed every 2-4 hours, in the dose that is 5-15% of the 24-hour baseline dose of the long-acting opioid.
SIDE EFFECTS
The most feared side effects of opioid analgesia are tolerance and addiction – both totally unsubstantiated by clinical evidence. In the vast majority of chronic pain sufferers, tolerance and addiction DO NOT occur. What is encountered more frequently is PSEUDOADDICTION – appropriate demand for adequate pain control.
Once the pain-relief dosage is established, it remains stable; if the disease progresses, or activity increases, titration to a higher stable dose is necessary. If rescue medication becomes unnecessary, or sedation appears, the dose can be slowly reduced.
Inadequately treated pain is a much more important cause of opioid tolerance than use of opioids themselves!
Other typical side effects are usually resolved within a few days to a week.
Respiratory Depression: clinical evidence shows clearly that this does not occur when the drug is titrated against the patient’s pain.
Nausea/Vomiting: occurs in 10-40% of pts, may require anti-emetics.
Sedation: if intolerable, dose reduction by 25% may be required.
Constipation: may be troublesome in over 50% of pts. Use bulk laxatives.
Pruritus: may require non-sedating anti-histaminics during the first week.
Myoclonus: very rare; benzos (clonazepam) useful.
Side effects – result of the stimulation of non-opioid receptors – can be ingeniously managed by adding a miniscule dose (0.001% of the usual dose) of an opioid antagonist (e.g. naltrexone) to the opioid treatment regimen.
Adding an NMDA or a CCK antagonist, or an alpha-2 adrenergic or GABA agonist, can frequently be effective in reducing the pain-relieving opioid dose.
SENSORY MODULATION
Included here are various interventions that either block or modify the sensory input. These interventions can be quite effective, esp. when combined with adequate drug analgesia. Local anesthetic blocks, including sympathetic blocks, can sometimes provide remarkable relief, lasting days and weeks. Physical and electrical stimulation can be effective, and hypertonic saline injections can sometimes provide long-lasting relief.
PSYCHOLOGICAL INTERVENTIONS
Affective and cognitive dimensions of pain can be manipulated through psychological techniques, thus providing better gate control to the sensory input. CBT has been widely used and found helpful, and so has hypnosis, which can differentially influence the perception of the pain intensity, and the pain unpleasantness. Social support is of paramount importance, too.
PLACEBO
The placebo effect in pain is easier to comprehend if one views pain not as a stimulus, but as a sequence of appropriate motor responses to deal with the noxious stimulus:
Appropriate action influences the affective-motivational and cognitive-evaluative dimensions of pain, thus potently activating the descending inhibitory controls.
PET and fMRI studies of patients receiving an active drug or a placebo, furnish proof of the placebo effect being mediated by the internal opioid system – showing increased blood flow to the opioid receptors-rich areas in the anterior cingulate and lower brainstem. This effect can be totally blocked by naloxone (opioid antagonist), and attenuated by CCK; on the other hand, it can be augmented by CCK antagonists.
REDEFINING PAIN
With this knowledge, let me elaborate now on a new perspective on pain, and provide a new definition of it.
It is well known that damage to the anterior cingulate cortex (Brodmann’s area 24) abolishes the generation of pain, despite activation of nociceptive pathways ("I feel the pain, but it doesn’t hurt").
Thus, we may assert that pain is an emotion, a construct given by the intrinsic activity of the brain. As such, pain is not localizable; it may seem localized because of co-activation of pain - the emotional state and general tactile stimulation.
"The unpleasantness of pain is an emotional state generated by the brain, not an event that somehow resides at a particular body location" (R.Llinas). This definition clearly implies that sensory pathways do not execute sensations; they only serve to inform the internal context (intrinsic activity of the brain) about the external world. In order to understand the states of pain, and devise more successful modes of pain treatment, it is imperative that we separate the carriers of sensory activity from the actual executors of sensation.
Only through this approach will we be able to avoid perpetuating the noxious errors of Cartesian dualism, and reduce needless suffering of millions of people in chronic pain.
In conclusion, I will reiterate "Few things a doctor does are more important than relieving pain"!
D.Z.FULGOSI, MD, FRCP(C)
CONCILIENCE HEALTH RESOURCES
Simple Sprain
The Lumbar Spine extends from L1 (adjacent to the thoracic spine) down to L5
where it connects with the sacral bone .
Simple Sprains usually occur when the low back is in a vulnerable position e.g.
bending forwards and bent to one side whilst lifting shopping out of the boot of
the car, or violent sneezing whilst bent forwards.
The sprained part is usually in the superficial part of the spine (muscle, joint
or ligament). The sprained tissue becomes inflamed, causing pain signals to be
sent to the spinal cord.
If the incoming pain signals are strong enough and go on for long enough,
processing centres (dorsal horn) in the spinal cord become sensitised, sending
out signals to the muscles in the vicinity of the sprain to contract to produce
muscle spasm. This is initially a protective reflex which may prevent further
injury to the sprained part.
If the muscles in the area are contracting quite strongly, then the tension
receptors in the local muscles and joints are activated. Strong signals from the
tension receptors can be interpreted in the spinal cord as pain, adding to the
pain signals from the inflamed tissue. These two kinds of signal combine
together to keep the spinal cord dorsal horn in a sensitized state, and also
keeping the spinal muscles in a contracted state through a feedback loop. The
sequence of events can be therefore summarized in the diagram below:-
Severe muscle spasm is a type of cramp, and like any other cramp in the body it
hurts, causing restricted painful back movements. Over a variable period of time
the initial back sprain heals, reducing the signals to the spinal cord, and also
reducing the degree of spinal cord dorsal horn sensitization. Once this
sensitization has declined, the outward signals to the muscles in the area of
the sprain also lessen, allowing the pain and muscle spasm to resolve naturally.
In about 10% of adults the back pain continues despite healing of the the
initially sprained area. In this situation there is a perpetual loop as shown
below, without there being any sprain or inflammatory process involved. This
situation may leave individuals susceptible to further sprains due to the back
muscles being in a contracted and shortened state, and also due to there being
pre-existing dorsal horn sensitization.
Peripheral tissue or nerve injuries can lead to biochemical and morphological changes within the corresponding area of the dorsal horn of the spinal cord. These changes can be longlasting and could account for the persistence of pain after the original insult has gone; they can also spread so that pain may be perceived as coming from a much wider area. Increased sensitisation of the dorsal horn may account for hyperpathia and allodynia. These changes could be responsible for the widespread sensitivity of the back and lower limbs to pressure commonly described by patients with chronic back pain. Descending impulses from the brain can also activate the sensitised dorsal horn so that a potential mechanism exists for integrating psychological distress and pain perception.12 Patients who are given centrally acting analgesics before operation complain of less severe postoperative pain and wound hyperalgesia.13 The possibility of reducing this central sensitisation has implications for treating back pain.
|
Peripheral sensitization causing decreased activation threshold of receptors and shortened response latency
this results in hyperalgesia
Fibers in the CNS are induced to carry nociceptive input without normal dorsal root inhibition
constant bombardment of CNS overwhelms filtering
Pain can actually cause muscle spasm and sympathetic outflow
CNS sensitization is called wind-up
PAIN: OF COURSE IT’S ALL IN YOUR HEAD
NEUROBIOLOGY OF PAIN
DEFINITION
IASP: "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Even the
authors were aware of this definition’s inadequacy, and hastened to add: "Pain is always subjective… This definition avoids tying pain to the stimulus".
Despite the disclaimer, this definition DOES tie the sensation to the stimulus, perpetuating the centuries old fallacy. It does not, and cannot, explain many of the
perplexing aspects of pain experience, and it does not consider the crucial influence of the brain on the sensation and the perception of pain.
1. The brain can generate pain, create a perceptual experience, independent of the peripheral input, i.e., regardless of the presence or the extent of tissue
damage or pathology.
2. The brain is continually modified by experience and sensory input.
THE PUZZLE OF PAIN
Without the contributions of modern neuroscience, it is impossible to unravel the multitude of the pain puzzles:
1. Well known instances of NO PAIN with major injuries
2. Excruciating PAIN in missing structures (phantom pains), or denervated structures (below spinal cord section in paraplegics)
3. PAIN persisting, after complete healing of injury
4. PAIN provoked by touch, or no stimulus at all
5. PAIN that is delayed, or non-anatomically spread
NOCICEPTION AND PAIN PATHWAYS
Stimuli from the periphery (mechanical, chemical, thermal) are transmitted to the spinal cord through the sensory afferent nerves.
Damaged tissue is a source of many amines and peptides that stimulate sensory nerve endings: bradykinin, adrenaline, 5HT, PGE2, IL-1, IL-6, TNF-alpha, etc.
These afferents synapse on the dorsal horn second order neurons in the spinal column (projection neurons), which form pathways extending to the brain – primarily
thalamus and somato-sensory cortex.
Acute, physiological pain is mediated in the spinal synapses mainly by the GLUTAMATE-activated AMPA type of glutamate receptors.
In addition to glutamate, excitatory transmitters include AcCh, substance P, and CGRP, while GABA, enkephalin, 5HT and NA provide the inhibitory
neurotransmission.
NEUROBIOLOGY OF CHRONIC PAIN
Chronic pain is not just a prolonged acute pain; it is a distinct entity, with many functional and structural alterations of the peripheral and central nervous system.
ERIPHERAL SENSITIZATION – PRIMARY HYPERALGESIA
Peripheral nociceptive hyperexcitability is induced through increased receptor (autosensitization) or cell membrane (heterosensitization) reactivity to stimuli, usually
sustained presence of inflammatory factors.
CENTRAL SENSITIZATION – SECONDARY HYPERALGESIA
Central hyperexcitability is the key process in the generation of chronic pain. It is mediated by NMDA-type of post-synaptic glutamate receptors, and it results in
transcriptional changes and manufacturing of the c-fos protein (the marker of central sensitization) in the second order dorsal horn projection neurons.
Repetitious and intense activation of the high-threshold C-fibers and AMPA post-synaptic receptors results in activation of the NMDA post-synaptic receptors
(through dislodging the Mg ions and opening the N and Ca channels to Ca influx) and the NMDA mediated WIND-UP phenomenon (augmented response of the
dorsal horn neurons to the same intensity stimuli).
Activation of the NMDA-receptors represents the first step in central sensitization, i.e., the transition from acute to chronic pain.
Knowing this makes it easy to realize that adequate treatment of physiological, nociceptive pain is the most important goal of acute pain management – prevention of
central sensitization!
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Other changes involved in central sensitization include substance P – NO (nitric oxide) cascade (with expansion of the receptive fields), increased release of NPY,
VIP, galanin, and somatostatin from the pre-synaptic C-fiber terminals, hyper-sensitization of the WDR (wide dynamic range) neurons to non-nociceptive stimuli,
expression of substance P by A-fiber pre-synaptic terminals, and sprouting of A-fiber terminals into the superficial layers of the dorsal horn (thus synapsing onto the
nociceptive second order neurons).
Reorganization or remodelling of the synapses at the dorsal horn level, as well as at the brainstem, thalamus, and somatosensory cortex levels, is a well-documented
phenomenon, referred to as neuronal plasticity, responsible for a variety of chronic pain syndromes.
Central sensitization and neuroplastic remodeling are responsible for all the main features of chronic pain: hypersensitivity to nociceptive stimuli (hyperalgesia),
perception of pain upon non-nociceptive stimulation (NNP and allodynia), expansion of the pain-receptive fields and trigger-zones, and delayed pain.
Changes in central sensitization can be viewed as:
1. FUNCTIONAL (NEUROCHEMICAL) HYPEREXCITABILITY:
Activation of the NMDA- receptors, wind-up, sensitization of WDR neurons, expression of substance P by A-fibers
2. STRUCTURAL (NEUROANATOMICAL) HYPEREXCITABILITY:
Dying-off of C-fiber terminals, sprouting of A-fiber terminals, extensive reorganization of the somatosensory cortical maps, remodeling in the
brainstem, cerebellum, basal ganglia, and motor cortical areas.
DYSFUNCTIONAL DESCENDING INHIBITION – FAILURE OF INTERNAL ANTINOCICEPTION
As illustrated in PAIN PATHWAYS, nociception activates not only the afferent pathways, but also a variety of segmental and descending, inhibitory or antinociceptive
pathways (SLIDE 5). Increased brainstem CCK, and deficiencies in the descending enkephalin, 5HT, and NA pathways, can all contribute to
dysfunctional anti-nociception.
Processing of pain at the brain level has profound implications for both, the perception of pain, and for the management of pain.
Ascending pain pathways are relayed through the thalamus to the somatosensory cortex, which is responsible for the initial localization and the intensity of the
stimulus (SENSORY-DISCRIMINATIVE function), as well as to the limbic brain structures, esp. the anterior cingulated cortex, which is responsible for the
unpleasant, aversive aspect of the experience (AFFECTIVE-MOTIVATIONAL function). Both of these areas communicate extensively and reciprocally with the
prefrontal cortex, which brings the situational and memory context to the experience (COGNITIVE-EVALUATIVE function).
These three aspects of pain experience (R. Melzack’s gate and neuromatrix theory of pain) make a variety of pain treatment modalities potentially helpful, and at the
same time provide the neurophysiological and neurostructural explanation of these modalities’ efficacy (dismissing, in the process, all kinds of hogwash that has been
written about "psychogenesis" of pain).
CHRONIC PAIN SYNDROMES
Chronic pain is generally categorized, according to etiological factors, as stemming from tissue damage –
inflammatory pain, or fromnerve damage –
neuropathic pain. The former is evident in various injuries (low back pain), infections, inflammatory diseases (RA, IBD, SLE) andimmune/neuroendocrine dysfunctions (possibly FM/CFS, MPS). The latter is encountered in diabetes, certain infections (shingles), cancer, traumatic nerve injury, and
following amputations (limb, breast).
Opioids are exceedingly effective in managing inflammatory pain, whereas they are less effective in managing neuropathic pain, due to the loss of pre-synaptic opioid
receptors, and the extensive re-wiring of the dorsal horn synaptic circuits.
Low back pain
In up to 85% of sufferers, there is no detectable damage ("no objectively demonstrable organic pathology"); in only about 15% can one of the five recognizable causes
(herniated disc, arthritis, infection, tumor or fracture) be demonstrated.
In addition, it is estimated that about 10% of low back pains develop a neuropathic dimension, making the picture even more puzzling. The vast majority of chronic
low back pain sufferers continue to be under-treated or maltreated, labeled as "somatizers" or malingerers, despite ample evidence for central sensitization and
somatosensory mapping reorganization in such patients.
Fibromyalgia and Myofascial Pain Syndrome
There is ample evidence in these disorders, as well, of altered central processing of the incoming nociceptive and non-nociceptive stimuli, at both the spinal and the
brain level. Incoming stimuli from muscle C-fiber afferents are much more potent inducers of central sensitization than skin afferents, explaining lower pain threshold
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(hyperalgesia) and pain on movement (proprioceptive allodynia) in these patients. In addition, a dysregulated neuroendocrine stress response (decreased cortisol,
growth hormone and IGF-1 secretion) may compound the picture in about a third of patients.
Phantom limb pain
Phantom pains affect over 70% of amputees, and persist for 2-7 years in about 60% of them; fewer than 15% obtain total pain relief. Extensive somatosensory cortex
reorganization, with expansion of the trigger zones, has been demonstrated in numerous brain imaging studies.
Peripheral ectopic discharges (from the stump neuroma), deafferentation hyperexcitability, and unmasking of the underlying silent connections, may all be
contributory.
In addition to phantom limb pain, phantom pains following mastectomy, and phantom body pains below the spinal cord section in paraplegics, are gaining increasing
recognition.
DIAGNOSIS OF CHRONIC PAIN: CARTESIAN DUALISM, PSYCHOBABBLE AND ARROGANT IGNORANCE
Clinical features of chronic pain can be confusing and difficult to comprehend for the examining physician, leading to the characterization of the patient’s complaints
as "non-organic", "psychogenic", "hysterical", "somatizing", and "hypochondriacal", or as evidence of "illness/pain behavior", "emotional overlay", or even
malingering.
Especially puzzling is:
Widespread regional or generalized pain
Easily provoked pain, by even a mild physical workload
Sense of peripheral muscular weakness and reduced endurance
Diffuse and transient sensory abnormalities (dysesthesia)
Regional or generalized hyperalgesia and/or allodynia, often with "jump-sign"
Hyperalgesic muscle trigger points, with distally referred pain and/or dysesthesia that do not follow segmental or neuroanatomical patterns of distribution
Delayed pain following physical examination, which may persist hours or daysThese features (we now recognize them as classical features of non-nociceptive pain) not only lead to the diagnosis of psychopathology (psychiatric or "functional"
illness), but, more importantly, create a poisonous atmosphere in which the patient is blamed for "needing or creating" his pain, and is deprived of the necessary and
effective treatment.
Thus, it is imperative to keep in mind that medically unexplained pain - pain with non-anatomical characteristics, or incongruent with observable pathology, is NOT
evidence of psychopathology. Frequently, the presence of psychological distress, and the elevated hysteria, hypochondriasis, and depression scales on the MMPI,
which are the consequences of pain, are cited as the cause of pain (despite evidence that they normalize with improvement in pain). As well, both the success and
failure of psychological treatment are attributed to psychological factors and "illness behavior".
Meanwhile, the challenge should remain for the modern-day Cartesian dualists to provide the empirical evidence and proof that psychopathology causes pain, and, in
so doing, to specify the mechanisms by which it does!
It is becoming increasingly apparent that the domain of the psychiatric "somatization" diagnosis is shrinking, as neuroscience keeps expanding our knowledge of NNP
(non-nociceptive pain) mechanisms.
We, as physicians, should heed the exhortations of the medical masters, past and present:
"Pain must be regarded as a disease… and the physician’s first duty is action – heroic action – to fight disease". (Benjamin Rush)
"Few things a doctor does are more important than relieving pain… pain is soul destroying. No patient should have to endure intense pain unnecessarily. The quality
of mercy is essential to the practice of medicine; here, of all places, it should not be strained". (Marcia Angell)
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TREATMENT OF CHRONIC PAIN
DRUGS
Historically, two herbs have provided humanity with pain relief: willow and poppy. Even today, 95% of the analgesics in use are derivatives of either ASA or opium.
ASA and NSAIDS are usually the first line approach to the treatment of chronic pain, esp. pain of inflammatory variety. When combined with opioids, they may have
a synergistic effect.
ANTIDEPRESSANTS have been used with varying degrees of success. The most commonly used ones are amitriptyline and trazodone, since they also enhance SWS
(slow-wave sleep, i.e., stage III and IV of sleep), a feature of particular advantage in treating fibromyalgia (cyproheptadine and zolpidem may be useful in this regard,
too). Many other antidepressants have been used, including, more recently, the dopaminergic ones. Bupropion has been found useful in some cases of neuropathic
pain.
ANTICONVULSANTS gabapentin and lamotrigine are generally used as the first line approach to the neuropathic pain.
GABA agonists are also of considerable value; baclofen – a GABA
B agonist – is particularly useful in treatment of spastic pains.AMPHETAMINES have been used in combination with opioids for treatment of severe, intractable pain.
ALPHA-2 AGONISTS – clonidine – are sometimes extremely effective and highly synergistic when combined with opioids.
SUBSTANCE P ANTAGONISTS have shown a potent analgesic effect in clinical trials, and at least one preparation should be available for general use soon.
Interestingly, this same agent has been quite effective as an antidepressant, as well.
CCK ANTAGONISTS – proglumide 200-250 mg p.o. – cancel CCK antagonism to opioids, augments opioid analgesia, and restores opioid effectiveness in
neuropathic pain.
NMDA-RECEPTOR ANTAGONISTS
Recognition of NMDA-receptors as mediators of chronic pain has opened up a huge area of research. Drugs that block these receptors have a glorious potential in the
treatment of chronic pain, esp. the neuropathic pain. When combined with opioids, they have a synergistic effect, and can restore opioid sensitivity in neuropathic
pain.
The currently available agents in N.America are ketamine (I.V. – 0.3mg/kg x 10 min.: substantial reduction in FM pain lasting 7 days), dextromethorphan (10-30
mg/kg B.I.D.), and amantadine, but two very promising agents in wide usage in Europe – flupirtine and memantine – should become available soon. Research on
ziconotide – a snail venom derivative – looks extremely promising.
OPIOIDS
The most effective by far, and the most feared and underutilized drugs in the treatment of chronic pain are the opioid analgesics. Prejudice, paranoia and ignorance
surrounding these drugs, are the main reasons behind the inadequate treatment of chronic pain and a colossal amount of unnecessary suffering that it causes.
The main effects of opioids (both external and internal) are achieved through stimulation of the
mu-opioid receptors. They amount to 70% of the spinal opioidreceptors, while the share of
delta and kappa receptors is about 25% and 5%, respectively.The vast majority of opioid receptors in the dorsal horn – about 70% of the total
mu-receptors – are located on the pre-synaptic terminals, where they potently inhibitthe release of glutamate and substance P from the C-fiber afferents. Post-synaptically, they cause membrane hyperpolarization (preventing the NMDA-receptor
activation and the wind-up phenomenon), while also stimulating the inhibitory GABA interneurons.
The loss of pre-synaptic
mu-receptors in injured or severed nerves, explains the reduced effectiveness of opioids in neuropathic pain.Opioid analgesia is usually initiated with the short half-life agents, given q 3-4 h:
Morphine 15-30 mg
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Codeine 30-60 mg
Oxycodone 10-15 mg
Hydrocodone 10-15 mg
Hydromorphone 2-4 mg
Caution: CYP 2D6 inhibition reduces the effectiveness of codeine, oxycodone and hydrocodone (preventing formation of active metabolites).
Once the effective drug is found (44% of patients required trials of 2 or more, while 20% required trials of 3 or more opioids), a sustained-release opioid is
substituted, in the same daily dosage, given b.i.d. or even o.d.
The 24-hour baseline dose, for sustained release opioids, is:
Morphine 60 mg
Codeine 200 mg
Oxycodone 30 mg
Hydrocodone 40 mg
Hydromorphone 7.5 mg
Methadone 20 mg
Levorphanol 4 mg
Fentanyl 25 microg transdermal patch, lasting 72 hours: equivalent to 45-135 mg/day of oral morphine; doesn’t pass through the liver, less constipation.
Oxycodone is the most utilized sustained-release opioid, due to fewer side-effects, easy titration and marked effectiveness in visceral pain (probably by added
stimulation of
kappa-receptors).Methadone and levorphanol are opioids with NMDA-antagonist effects, but are difficult to titrate, and exhibit delayed-onset side-effects, esp. sedation.
Every patient on sustained-release agents should be provided with RESCUE MEDICATION – a fast-acting opioid to treat BREAK-THROUGH pain; this may be
needed every 2-4 hours, in the dose that is 5-15% of the 24-hour baseline dose of the long-acting opioid.
SIDE EFFECTS
The most feared side effects of opioid analgesia are tolerance and addiction – both totally unsubstantiated by clinical evidence. In the vast majority of chronic pain
sufferers, tolerance and addiction DO NOT occur. What is encountered more frequently is PSEUDOADDICTION – appropriate demand for adequate pain control.
Once the pain-relief dosage is established, it remains stable; if the disease progresses, or activity increases, titration to a higher stable dose is necessary. If rescue
medication becomes unnecessary, or sedation appears, the dose can be slowly reduced.
Inadequately treated pain is a much more important cause of opioid tolerance than use of opioids themselves!
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Other typical side effects are usually resolved within a few days to a week.
Respiratory Depression: clinical evidence shows clearly that this does not occur when the drug is titrated against the patient’s pain.
Nausea/Vomiting: occurs in 10-40% of pts, may require anti-emetics.
Sedation: if intolerable, dose reduction by 25% may be required.
Constipation: may be troublesome in over 50% of pts. Use bulk laxatives.
Pruritus: may require non-sedating anti-histaminics during the first week.
Myoclonus: very rare; benzos (clonazepam) useful.
Side effects – result of the stimulation of non-opioid receptors – can be ingeniously managed by adding a miniscule dose (0.001% of the usual dose) of an opioid
antagonist (e.g. naltrexone) to the opioid treatment regimen.
Adding an NMDA or a CCK antagonist, or an alpha-2 adrenergic or GABA agonist, can frequently be effective in reducing the pain-relieving opioid dose.
SENSORY MODULATION
Included here are various interventions that either block or modify the sensory input. These interventions can be quite effective, esp. when combined with adequate
drug analgesia. Local anesthetic blocks, including sympathetic blocks, can sometimes provide remarkable relief, lasting days and weeks. Physical and electrical
stimulation can be effective, and hypertonic saline injections can sometimes provide long-lasting relief.
PSYCHOLOGICAL INTERVENTIONS
Affective and cognitive dimensions of pain can be manipulated through psychological techniques, thus providing better gate control to the sensory input. CBT has
been widely used and found helpful, and so has hypnosis, which can differentially influence the perception of the pain intensity, and the pain unpleasantness. Social
support is of paramount importance, too.
PLACEBO
The placebo effect in pain is easier to comprehend if one views pain not as a stimulus, but as a sequence of appropriate motor responses to deal with the noxious
stimulus:
1. Escape – from the noxious source, remove the source
2. Guard – assume protective posture, immobilize; to allow healing
3. Seek cure or remedy – go to healers, shamans, physicians
Appropriate action influences the affective-motivational and cognitive-evaluative dimensions of pain, thus potently activating the descending inhibitory controls.
PET and fMRI studies of patients receiving an active drug or a placebo, furnish proof of the placebo effect being mediated by the internal opioid system – showing
increased blood flow to the opioid receptors-rich areas in the anterior cingulate and lower brainstem. This effect can be totally blocked by naloxone (opioid
antagonist), and attenuated by CCK; on the other hand, it can be augmented by CCK antagonists.
REDEFINING PAIN
With this knowledge, let me elaborate now on a new perspective on pain, and provide a new definition of it.
It is well known that damage to the anterior cingulate cortex (Brodmann’s area 24) abolishes the generation of pain, despite activation of nociceptive pathways ("I feel
the pain, but it doesn’t hurt").
Thus, we may assert that
pain is an emotion, a construct given by the intrinsic activity of the brain. As such, pain is not localizable; it may seem localized becauseof co-activation of pain - the emotional state and general tactile stimulation.
"The unpleasantness of pain is an emotional state generated by the brain, not an event that somehow resides at a particular body location" (R.Llinas). This definition
clearly implies that sensory pathways do not execute sensations; they only serve to inform the internal context (intrinsic activity of the brain) about the external world.
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In order to understand the states of pain, and devise more successful modes of pain treatment, it is imperative that we separate the carriers of sensory activity from the
actual executors of sensation.
Only through this approach will we be able to avoid perpetuating the noxious errors of Cartesian dualism, and reduce needless suffering of millions of people in
chronic pain.
In conclusion, I will reiterate
"Few things a doctor does are more important than relieving pain"!D.Z.FULGOSI, MD, FRCP(C)
CONCILIENCE HEALTH RESOURCES
Opiates are natural deriviatives of opium plant, opioids are related
Three opioid receptors:
mu (u)
supraspinal and spinal analgesia, euphoria, resp depression, decreased gut motility, physical dependance
kappa (k)
supraspinal and spinal analgesia, but dysphoria
delta (b)
agonism produces spinal analgesia
not many currently available drugs hit these, all endogenous
nalaxone, give 2/3s of required dose to reverse resp depression hourly as a drip
t 1/2 1 hour
naltrexone
orally peak concentrations 1-2 hours, t 1/2 3 hours, duration of 24 hours
inflammatory soup sensitizes peripheral nociceptors
windup DRG and cord stimulation lead to increased sensitization
GABA may inhibit this process
CNS is able to down modulate this sensitization
can also facilitate it
Keorolac 30 mg IV 60 mg IM
print 356-365
Sanjay Arora, MD;* Jonathan G. Wagner, BA;† Mel Herbert, MD, MB BS, BMedSci‡
*Clinical Instructor of Emergency Medicine and Assistant Residency Director, Keck School of Medicine, Los Angeles County + University of Southern California (LAC+USC) Department of Emergency Medicine, Los Angeles, Calif. †Keck School of Medicine, LAC+USC Department of Emergency Medicine, Los Angeles, Calif. ‡Associate Professor of Medicine, Keck School of Medicine, LAC+USC Department of Emergency Medicine, Los Angeles, Calif.
Can J Emerg Med 2007;9(1):30-2
Acute pain is an extremely common presenting symptom to the emergency department (ED), making it imperative that emergency physicians provide adequate, safe and cost-effective analgesia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are often first-line treatments for moderate to severe pain. Physicians can choose between intramuscular (IM) or intravenous (IV) ketorolac and an oral NSAID. The mechanism of action (reversible inhibition of prostaglandin synthesis at the level of cyclooxygenase) is identical irrespective of the route the medication is given.1 Despite the similar pharmacodynamics, many physicians believe that parenteral ketorolac is more efficacious, despite a greater cost and a more invasive route of administration. To investigate this myth (i.e., that parenteral ketorolac provides greater analgesic effect than an oral NSAID), we conducted a review of the literature, with specific focus on ibuprofen as the prototypical — and least expensive — oral NSAID.
The terms "ketorolac" and "ibuprofen" were searched in MEDLINE and PubMed, revealing 17 and 67 articles, respectively. Articles were limited to English language and those involving human subjects. All abstracts were reviewed. Articles directly comparing oral ibuprofen with IM or IV ketorolac were included. To ensure no important papers were missed, an ancestral search of identified articles was also performed.
In 1994, Wright and associates evaluated the effectiveness of a single dose of 800 mg of oral ibuprofen (n = 95) versus 60 mg of IM ketorolac (n = 70). This was a retrospective analysis of data collected during a prior prospective survey of pain management efficacy, in patients presenting to the ED with acute pain due to a large variety of causes.2 Using the 100-mm visual analog pain scale (VAS) they found a mean score reduction of 34 in the ibuprofen group and 35 in the ketorolac group. They concluded that the 2 have almost identical efficacy in those presenting with acute pain of varied sources, and that unless oral administration is contraindicated, ibuprofen is superior given its ease of administration, its significantly lower cost, and the lack of pain associated with administration.2
In 1995, Turturro and colleagues compared 800 mg of oral ibuprofen with 60 mg of IM ketorolac in a prospective, double-blind, randomized trial of 82 patients presenting to the ED with acute traumatic musculoskeletal pain.3 They used the 100-mm VAS to quantify pain at baseline, 15, 30, 45, 60, 75, 90 and 120 minutes post dosing. They found no significant differences in mean pain scores at baseline or at any time point throughout the 2-hour period. They noted that the ibuprofen group exhibited lower mean pain scores in the later intervals of the study; however, it was not statistically different. They concluded that oral ibuprofen and IM ketorolac provide similar analgesia with similar onset of action in minor-to-moderate acute musculoskeletal pain and reasoned that IM ketorolac should be reserved for those patients with contraindications to oral intake due to its painful administration and its higher cost (170 times that of ibuprofen at their institution at the time of the study).3
In yet another prospective, randomized, double-blind study in the ED, Neighbour and Puntillo investigated the analgesic efficacy of 60 mg of IM ketorolac versus 800 mg of oral ibuprofen in patients with self-assessed pain scores of 5, 6, 7 or 8 on a numerical rating scale of 0-10 (0 corresponding to "no pain" and 10 corresponding to "worst possible pain") for a variety of pain etiologies.4 Patients' pain levels were assessed at 0, 15, 30, 45, 60, 90 and 120 minutes after administration of analgesic. They found no statistical differences in pain levels between study groups at any time point in the study, further emphasizing conclusions reached in the 2 prior ED studies.
In a 1998 prospective, randomized, double-blind study conducted in surgical patients, Mixter and coworkers investigated the use of 60 mg of IV ketorolac at the time of trocar insertion versus 800 mg of oral ibuprofen 1 hour before surgery in laparoscopic hernia repairs.5 All patients were discharged within 5 hours of completion of surgery, and patients were instructed to take ibuprofen 400 mg orally every 4 hours for 24 hours regardless of pain level. They measured pain using the 100-mm VAS at time of discharge and found no significant difference between the ketorolac group (VAS = 35) and the ibuprofen group (VAS = 30). They also measured pain 18 hours after discharge, and found an identical score in the 2 groups (VAS = 20). Like the previous ED studies comparing the 2 drugs, the authors concluded that oral ibuprofen offers equal pain control at lower cost and reduced potential for adverse drug events for post-surgical patients.5
Interestingly, in one of the first studies comparing ketorolac with ibuprofen in post-op patients, Morrison and Repka did find a significant difference in pain control.6 In this prospective, randomized, double-blind study, they compared a single dose of 60 mg of IV ketorolac intraoperatively (n = 20) with a single dose of 600 mg of ibuprofen 30-45 minutes after completion of strabismus surgery (n = 20). Pain was assessed with the 100-mm VAS. At 2 hours post-op, the VAS for ketorolac patients was 15 and for the ibuprofen patients it was 50. At 5 hours post-op, the VAS for ketorolac patients was 20 and for the ibuprofen patients it was 44. They concluded that IV ketorolac was more effective than oral ibuprofen in controlling postoperative pain in patients undergoing strabismus surgery. However, the study design needs further scrutiny before taking this data at face value: there were multiple methodological flaws, and the results, as the authors themselves point out, should be interpreted with caution.6 In their study, the oral ibuprofen was not distributed in its commercially available formulation; instead, it was crushed and administered in unmarked capsules, which may have altered the analgesic's pharmacodynamics. Even more importantly, in the protocol IV ketorolac was given at least 30-45 minutes before the oral ibuprofen was administered. Multiple studies have shown that as patients receive repetitive painful stimuli over time without analgesia, the overall total perception of pain significantly increases.7,8 Those patients in this study receiving oral ibuprofen late in the course of their care had time to suffer from this so-called "wind-up" phenomenon, which is a complex neurotransmitter-based phenomenon that results in "pain begetting pain."9 It is impossible to draw conclusions from a study comparing the efficacy of 2 drugs when the oral format was given well after the IV preparation. A balanced study would instead have allowed the oral format to be given prior to the IV one.
The studies discussed in this paper dealt with patients who had a wide variety of pain syndromes, but there is some anecdotal evidence and a limited number of published studies touting the efficacy of parenteral ketorolac when used specifically for the treatment of renal colic. It has been shown in multiple studies that ketorolac is as good as, if not better than, low dose meperidine in providing effective pain relief in renal colic.10-14 Similar results were found in studies comparing the efficacy of ketorolac with diclofenac in patients with renal colic.15,16 Safdar and colleagues compared ketorolac to morphine for the treatment of acute renal colic using a prospective randomized, controlled, double-blinded design.17 Patients received either 5 mg of IV morphine or 15 mg of IV ketorolac at time zero with a repeat dose of the same at 20 minutes. A third group received both agents at both time intervals. They found no significant difference in efficacy between the ketorolac and morphine groups in relief of pain, but did find a significant reduction in pain in the combination group. They therefore concluded that a combination of morphine and ketorolac provides greater analgesia than using either of the agents alone.18 Despite the plethora of trials comparing ketorolac with narcotics and proving the utility of NSAIDs for the treatment of renal colic, there are no identifiable studies comparing parenteral ketorolac with oral ibuprofen in this setting. It is quite possible that, as in the treatment of other acute pain syndromes, ibuprofen may provide equal analgesia. Given that vomiting is frequently a part of the presentation of renal colic, a parenteral NSAID may be preferred.
Many physicians continue to administer IM or IV ketorolac regardless of the aforementioned studies, perhaps due to the belief that patients respond better to parenteral analgesia because the patients consider them "stronger" medicines. Schwartz and associates investigated this perceived placebo effect in a fascinating prospective, randomized, double-blind study in which patients were unknowingly given 800 mg oral ibuprofen in a flavoured drink and then given either a placebo IM injection or a placebo pill. In this interesting study design, neither group received IM medication. They found no significant difference in pain reduction via the VAS and concluded that the use of IM administration of NSAIDs for pure placebo effect appears unwarranted.18
In addition to a lack of improved efficacy and no benefit from a placebo injection effect, there are potentially serious downsides to this tactic. First, there is the risk of a needle-stick injury to health care personnel from unnecessarily using a parenteral medication when an oral form will work just as well. Second, even though all NSAIDs have the potential to exacerbate renal dysfunction, parenteral ketorolac seems particularly potent in this regard. In fact, in several European countries the 60-mg form of ketorolac was taken off the market due to its association with acute renal failure. It is also interesting to note that the manufacturer suggests that the oral dose of ketorolac be 10 mg but the parenteral form be 30-60 mg. Which other drug has a higher dose when given parenterally than orally? The exact implications of this dosing conundrum remain unclear, although an unacceptably high risk of gastrointestinal adverse events is felt to be the root cause of the lower oral dose.
The higher cost of ketorolac, the pain and difficulty associated with its administration, the risk of extravasation, and the exposure of practitioners to possible needle-stick injuries, all argue that there is no use for IM or IV ketorolac over oral ibuprofen in the ED for routine analgesia, unless oral administration of ibuprofen is unfeasible or contraindicated. Only in specific acute pain syndromes associated with nausea and vomiting, like renal colic, may its use be warranted. The belief that IM/IV medications are perceived as being stronger than oral medications and therefore result in a more powerful placebo effect has also been shown to be false. Wi
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