1 . The function of free nerve endings (FNEs) is to transmit information regarding
| A) | | stretch. |
| B) | | pressure. |
| C) | | pain and temperature. |
| D) | | three-dimensional location. |
TYPES OF SENSORY RECEPTORS
| Type | Function | Location |
|---|
| Free nerve ending | Transmit pain and temperature | Skin, periosteum, arterial walls, joint surfaces |
| Pacinian (lamellar) corpuscle | Pressure | Skin |
| Meissner (tactile) corpuscle | Touch | Skin |
| Muscle spindle | Stretch and pressure | Skeletal muscle |
| Golgi tendon apparatus | Stretch and pressure | Tendons |
| Kinesthetic receptor | Three-dimensional location (proprioception) | Joints |
2 . Action potentials are
| A) | | cerebral responses to noxious stimuli. |
| B) | | the contraction and relaxation of the muscle fiber. |
| C) | | the capacity of nerves to perceive and transmit sensations of pain. |
| D) | | changes in polarity along a nerve based on ion flow into and out of the nerve cell. |
Action potentials are changes in polarity along a nerve based
on ion flow into and out of the nerve cell. As the action potential travels down the length
of the cell, it will end at a point in the nervous system that results in some form of
output, either physical (muscle movement) or experiential (pain). Figure
2 shows some of the details of an action potential and
provides an extended explanation of their formation. Of particular importance is the
quantity of ions moving at any specific time. The primary ions moving after stimulation and
reaching threshold are Na+ (sodium, into the cell), K+ (potassium, out of the cell), and Cl-
(chloride, into the cell). After the nerve has fired, the sodium/potassium adenosine
triphosphate (ATP)-ase pump works to move sodium out of the cell and potassium back into the
cell. A pump is needed because the ions are moving against their gradients, and energy is
required in the form of ATP to power the pump.
3 . What are the two primary types of nerves that carry pain data elicited by stimulation of an FNE?
| A) | | Mu and kappa types |
| B) | | Cardiac and smooth types |
| C) | | Compact and cancellous types |
| D) | | Type A-delta or myelinated and type C or unmyelinated |
There are two primary types of nerves that carry pain data
elicited by stimulation of an FNE: type Aδ or myelinated (fast) nerve fibers and type C or
unmyelinated (slow) nerve fibers [5,8]. Myelinated fibers are insulated with
Schwann cells, but with gaps (nodes of Ranvier) in which the nerve fiber is exposed to the
environment of the extracellular fluid. The myelinated fibers are also referred to as fast
fibers because the action potentials can skip between the nodes of Ranvier in a process
called saltatory conduction (rather than traveling the entire length of the axon). Sharp or
acute pain, especially from traumatic injury, is usually processed in this fashion.
4 . At what point does a first-order neuron synapse with a second-order neuron?
| A) | | In every FNE |
| B) | | The thalamus |
| C) | | The sensory cortex in the brain |
| D) | | The dorsal root of the spinal cord |
Pain and other impulses originate in the peripheral nervous
system (PNS), enter the dorsal horn of the vertebra, and then ascend to the brain along the
spinothalamic tract. This is a three-neuron pathway containing first-, second-, and
third-order neurons. In Figure 4, the
spinothalamic tract can be traced from the primary afferent nerve (receiving the pain
signals at the site of injury) to the spinal cord, entering via the dorsal root of the cord.
At this point, the first-order neuron synapses with a second-order neuron. Upon entry into
the cord, the second-order neuron crosses from the right to the left (or left to right, if
it enters the left dorsal root). This is referred to as decussation. The second-order neuron
then rises up the cord in either the anterior or later spinothalamic tract, synapsing with a
third-order neuron in the thalamus. This neuron leads to the sensory cortex in the brain,
which in turn interprets the exact location and degree of pain.
5 . Glutamate
| A) | | is an endogenous and highly excitatory neurotransmitter that binds at both the NMDA and AMPA receptors. |
| B) | | increases synaptic excitatory transmission in neurons and are represented by such substances as TNF and interleukins. |
| C) | | is a broad family of neuropeptides, including substance P, neurokinin A, and neurokinin B, released in response to pain or inflammation. |
| D) | | is a ubiquitous substance throughout the body that is released by mast cells and binds with excitatory receptors on the neurons and other cells. |
SUBSTANCES AFFECTING THE TRANSMISSION OF IMPULSES IN FREE NERVE ENDINGS AND SOMATIC
NERVES
| Substance | Description |
|---|
| Bradykinin | Bradykinin is a vasodilator that increases capillary permeability, increases
migration of white blood cells, and increases free radicals in inflamed tissue and
significantly excites pain receptors. |
| Calcitonin gene-related peptide (CGRP) | Stimulation of the free nerve endings results in the release of CGRP from the
neuron, sensitizing it to stimuli and making the neuron hyperactive. |
| Norepinephrine | Pain stimulates the sympathetic nervous system, leading to the release of
norepinephrine, which has an excitatory effect on the neuron. |
| Glutamate | Glutamate is an endogenous and highly excitatory neurotransmitter that binds
at both the NMDA and AMPA receptors to excite the neuron and facilitate pain
transmission. |
| Histamine | A ubiquitous substance throughout the body, histamine is released by mast
cells and binds with excitatory receptors on the neurons and other cells. |
| Tachykinin | Tachykinins are a broad family of neuropeptides, including substance P,
neurokinin A, and neurokinin B, released in response to pain or inflammation. They
bind with neurokinin receptors, resulting in increasing excitatory stimulation of
the neuron. |
| Serotonin (5-HT) | During inflammation, 5-HT is released from platelets in the area of injury.
In turn, these bind with 5-HT2A and 5-HT3 receptors, resulting in excitation of
the nerve. |
| Prostaglandin | One of the most crucial substances in pain management, prostaglandin
sensitizes all aspects of excitatory phenomena in neurons. They are produced from
the cell's arachidonic acid supply via the cyclo-oxygenase and lipoxygenase
pathways. |
| Cytokine | Cytokines increase synaptic excitatory transmission in neurons and are
represented by such substances as TNF and interleukins (e.g., IL-1b,
IL-6). |
| AMPA =
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, NMDA = N-methyl-D-aspartate, TNF = tumor necrosis
factor. |
6 . The projection of the neurons into what area of the brain accounts for the suffering aspect of pain, where the sensation is overlaid with an emotional experience?
| A) | | The brainstem |
| B) | | The cerebellum |
| C) | | The limbic system |
| D) | | The cerebral cortex |
The thalamus also has neuronal branches that help to
stimulate the reticular activating system, the portion of the brain responsible for sleep
and waking [5]. The thalamus has numerous
projections into other areas of the brain, including the prefrontal cortex and the
amygdala, the latter of which is part of the limbic system [16,17]. The projections of the neurons into the limbic system account for the
suffering aspect of pain, where the sensation is overlaid with an emotional experience. As
pain is important in preventing homeostasis damage, including an emotional response to
pain (in addition to a sensory response) helps ensure the person experiencing pain will
avoid the stimulus that led to the pain.
7 . Hyperalgesia is the
| A) | | lack of response to normally painful stimulus. |
| B) | | exaggerated painful response to a painful stimulus. |
| C) | | painful response from a non-pain-inducing stimulus. |
| D) | | excessive release of pain-mediating substances in the body. |
Pain pathways stimulate many areas of the brain. The brain
responds by the release of many neurotransmitters and other hormones to provide a systemic
response [10]. As discussed, pain impulses
activate the amygdala, which triggers a sympathetic nervous system response, sometimes
referred to as the "fight-or-flight" response. The release of norepinephrine and epinephrine
results in, among other things, tachycardia, hypertension, and elevated blood glucose
levels. Additionally, the local response to the stimulus produces the release of local
neurotransmitters, such as substance P, glutamate, CGRP, and brain-derived neurotrophic
factor (BDNF) [10,11]. Of perhaps greater concern is the release
of cytokines, which results in a profound inflammatory response. The inflammatory response
is usually highlighted by hyperalgesia (exaggerated painful response to a painful stimulus)
and allodynia (painful response from a non-pain-inducing stimulus). Take the example of a
minor sunburn. If the skin is reddened and inflamed, a pat on the back becomes inordinately
painful (hyperalgesia) and simply wearing a shirt may be intolerable (allodynia). In
addition to these responses, untreated acute pain may lead to the expression of additional
FNEs and nociceptors.
8 . Nociceptive pain is
| A) | | a physiologic response to tissue injury. |
| B) | | the result of central nervous system injury. |
| C) | | strictly pathologic and has no adaptive function. |
| D) | | a perception that arises from activation of the immune response. |
Nociceptive pain is a physiologic response to tissue injury,
the perception that arises from intense stimulation of specialized peripheral sensory
neurons (nociceptors) that respond only to noxious (pain) stimuli. Nociceptive pain is
subgrouped by location of involved tissues into somatic pain (muscle or connective tissue)
and visceral pain (visceral structures) [38]. Nociceptive pain is considered adaptive during tissue healing but maladaptive and
pathologic when it persists after healing has occurred.
9 . Which of the following is an example of a centralized pain syndrome?
| A) | | Cancer pain |
| B) | | Fibromyalgia |
| C) | | Postsurgical pain |
| D) | | Postherpetic neuralgia |
Centralized pain results from heightened nociceptive
sensitivity in the absence of detectable peripheral stimulus and with negligible peripheral
inflammatory pathology. The mechanism is poorly understood and is regarded as strictly
pathologic as it lacks any evident adaptive function. Centralized pain disorders include
conditions such as fibromyalgia, tension headache, and irritable bowel syndrome [32,38,40].
10 . Which of the following drug classes acts on descending pain pathways?
| A) | | Opioids |
| B) | | Antidepressants |
| C) | | Local anesthetics |
| D) | | Nonsteroidal anti-inflammatory drugs (NSAIDs) |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
11 . The three primary opioid receptor types are
| A) | | mu, kappa, and delta. |
| B) | | alpha, beta, and delta. |
| C) | | mu, theta, and omega. |
| D) | | mu, sigma, and gamma. |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
Naturally occurring opioid compounds are produced in plants
(e.g., opium, morphine) and in the body (the endogenous opioids) [43]. Endogenous opioids are peptides that bind
opioid receptors, function as neurotransmitters, and help regulate analgesia, hormone
secretion, thermoregulation, and cardiovascular function. The three primary endogenous
opioid peptide families are the endorphins, enkephalins, and dynorphins, and the three
primary opioid receptor types are mu, kappa, and delta [44,45]. A quick overview of
this complex pain modulation system is helpful in understanding how opioid analgesics
work.
12 . Opioid antagonists are FDA-approved for the treatment of
| A) | | opioid overdose. |
| B) | | opioid-induced constipation. |
| C) | | alcohol and opioid use disorders. |
| D) | | All of the above |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
In addition to opioid-induced constipation, opioid
antagonists are U.S. Food and Drug Administration (FDA)-approved for the treatment of
alcohol and opioid use disorder (naltrexone 50–100 mg/day oral) and opioid overdose
(naloxone 0.4–1.0 mg/dose IV or IM). In pain medicine, the dose ranges of naltrexone and
naloxone are substantially lower. Of the two, naltrexone is much more widely used, and
published pain medicine studies have used dose ranges of 1–5 mg (termed "low-dose") or
<1 mg in microgram amounts (termed "ultra-low-dose") [65]. For example, case studies have reported dramatic improvement in
refractory pain with intrathecal administration of an opioid agonist combined with
ultra-low-dose naloxone in the low nanogram range [68].
13 . NSAIDs alleviate pain by
| A) | | inactivation of voltage-gated sodium channels. |
| B) | | modulation of collapsin-response mediator protein 2. |
| C) | | inhibiting the conversion of arachidonic acid to prostaglandins catalyzed by COX isozymes. |
| D) | | selective binding to and blockade of the alpha-2/delta-1 subunit of voltage-gated calcium channels. |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
NSAIDs alleviate pain by inhibiting the conversion of
arachidonic acid to prostaglandins catalyzed by COX isozymes. Nonselective NSAIDs inhibit
COX-1 and COX-2 and include ibuprofen, aspirin, and naproxen. The nonselective action
inhibits the formation of both gastroprotective-mediating prostaglandins and pain-promoting
prostaglandins, increasing the risk of serious toxicities such as GI ulceration and
bleeding. This prompted the development of selective COX-2 inhibitors, which produce fewer
GI side effects but are linked with an increased risk of cardio-renal morbidities [71]. To mitigate risk of GI adverse events,
proton pump inhibitors are recommended for use in some patients using NSAIDs [72].
14 . Diclofenac is available in all of the following routes, EXCEPT:
| A) | | Oral |
| B) | | Subcutaneous |
| C) | | Topical gel |
| D) | | Intravenous |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
COMMONLY USED NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) AND ACETAMINOPHEN
| Drug | Route(s) |
|---|
| Meloxicam (Anjeso) | IV, PO |
| Ketorolac (Toradol) | PO, IM, IV, eye drops, nasal spray |
| Ibuprofen (Motrin, Advil) | PO, IV |
| Diclofenac (Cataflam, Voltaren) | PO, IM, IV, eye drops, topical gel |
| Acetaminophen (Tylenol) | PO, IV, rectal |
| Naproxen (Aleve, Anaprox) | PO |
| Celecoxib (Celebrex, Elyxyb) | PO |
| Aspirin | PO |
15 . The maximum dose of lidocaine administered with epinephrine is
| A) | | 7 mg. |
| B) | | 125 mg. |
| C) | | 300 mg. |
| D) | | 500 mg. |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
MAXIMUM DOSES OF LOCAL ANESTHETICa
| Local Anesthetic | Ester or Amide | Maximum Dose Per Kilogram Plain | Maximum Dose Plainb | Maximum Dose Per Kilogram with Epinephrine | Maximum Dose with Epinephrineb |
|---|
| Bupivacaine (Marcaine) | Amide | 2 mg/kg | 175 mg | 3 mg/kg | 225 mg |
| Levobupivacaine (Chirocaine) | Amide | 2 mg/kg | 200 mg | 3 mg/kg | 225 mg |
| Lidocaine (Xylocaine) | Amide | 5 mg/kg | 350 mg | 7 mg/kg | 500 mg |
| Mepivacaine (Carbocaine) | Amide | 5 mg/kg | 350 mg | 7 mg/kg | 500 mg |
| Ropivacaine (Naropin) | Amide | 3 mg/kg | 200 mg | 3 mg/kg | 500 mg |
| Prilocaine (Citanest) | Amide | 6 mg/kg | 400 mg | 8 mg/kg | 250 mg |
| Procaine (Novocaine) | Ester | 7 mg/kg | 1,000 mg | 10 mg/kg | 600 mg |
| Tetracaine (Amethocaine) | Ester | 0.2 mg/kg | 20 mg | N/A | 1,000 mg |
| aDoses vary by country and institution,
familiarize yourself with your local policies regarding maximum doses before
administering | | bIf administering a local anesthetic to a large
patient, stop at the maximum dose, even if the mg/kg dose would exceed
it. |
|
16 . Which of the following statements regarding calcium channel blockers is TRUE?
| A) | | Gabapentin is absorbed linearly. |
| B) | | Gabapentin possesses a longer half-life than pregabalin. |
| C) | | Pregabalin is easier to titrate and better tolerated than gabapentin. |
| D) | | All of the above |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
The gabapentinoids, gabapentin and pregabalin, are widely
used in the management of both postoperative and chronic pain relief. Their names may give
the impression they interact with gamma-amino butyric acid (GABA), but this is not the case
[86,87]. Gabapentin and pregabalin are anticonvulsants that are also effective
in a wide range of neuropathic pain conditions. Their mechanism of action involves selective
binding to and blockade of the α2δ1 subunit of voltage-gated calcium channel in various
brain regions and the superficial dorsal spine. This inhibits the release of glutamate,
norepinephrine, and substance P to decrease spinal cord levels of neurotransmitters and
neuropeptides [76,88,89]. The binding affinity of pregabalin for the calcium channel α2δ1 subunit
is six times greater than gabapentin, which is reflected in the greater efficacy of
pregabalin at lower doses. Because gabapentin possesses a shorter half-life and nonlinear
absorption, pregabalin is easier to titrate and better tolerated [89].
17 . All of the following are alpha-adrenergic agonists, EXCEPT:
| A) | | Clonidine |
| B) | | Tizanidine |
| C) | | Nitrous oxide |
| D) | | Dexmedetomidine |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
While more commonly associated with the autonomic nervous
system and its functions, alpha-adrenergic agonists can also function in the relief of pain,
as well as decreasing the sympathetic side effects which accompany pain, including
hypertension and tachycardia. Antinociceptive activity of the α-2 adrenoceptor agonists
clonidine and tizanidine includes modulating dorsal horn neuron function and norepinephrine
and 5-HT release, potentiating mu-opioid receptors, and decreasing neuron excitability
through calcium channel modulation [92].
Clonidine is available as a transdermal patch for use in neuropathic pain states. Local use
enhances release of endogenous enkephalin-like substances. Intrathecal or epidural
administration with opioids and/or local anesthetics is favored in treating neuropathic pain
because the synergistic effect improves pain control. Tizanidine is used as a muscle
relaxant and antispasticity agent; its use in the management of musculoskeletal pain is off
label [76,79].
Dexmedetomidine was originally approved as a short-term
sedative analgesic for mechanically ventilated patients in the intensive care unit [93]. Dexmedetomidine is far more selective as
an alpha-adrenergic agonist and has the same central action around the locus coeruleus [93]. As time passed since its introduction, the
use of dexmedetomidine has increased, especially among patients with comorbidities (e.g.,
heart and vascular disease, morbid obesity). Its cardiovascular stability, along with its
minimal effect on respiratory drive after the infusion is terminated, have made this agent
popular in both the intensive care unit and the operating room. Aside from its use as a
sedative or aesthetic agent, use of dexmedetomidine has been explored in patients with
refractory end-of-life pain. In a case study, a male patient, 58 years of age, with chronic
pancreatitis secondary to alcoholism reported inadequate pain relief despite receiving a
combination of oxycodone, nortriptyline, and lorazepam. Increased inpatient intravenous
opioids and ketamine still brought the patient no relief, and dexmedetomidine was attempted
as a last resort. An infusion of dexmedetomidine brought the patient's pain under greater
control, to the extent that he was able to sit in a recliner and visit with family [94]. Based on this and other reports,
dexmedetomidine is being explored as a possible option in palliative care.
18 . The mechanism of action of ketamine primarily involves
| A) | | NMDA receptor inhibition. |
| B) | | modulation of dorsal horn neuron function. |
| C) | | blockade of Na+ influx of voltage-gated ion channels in afferent neuron terminals. |
| D) | | selective binding to and blockade of the alpha-2/delta-1 subunit of voltage-gated calcium channel. |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
Ketamine is a phencyclidine anesthetic given parenterally,
neuraxially, nasally, transdermally or orally in subanesthetic doses to alleviate a
variety of pain conditions, including severe acute pain, chronic or neuropathic pain, and
opioid tolerance [79]. The mechanism of
analgesic effect primarily involves NMDA receptor inhibition. Thus, patients with
NMDA-mediated central sensitization are likely to realize significant benefit from
treatment with ketamine. Ketamine also has activity on nicotinic, muscarinic, and opioid
receptors and exerts both anti-nociceptive and anti-hyperalgesic effects, with the latter
produced at lower dose ranges [98].
19 . Which of the following is NOT a serotonergic and noradrenergic re-uptake inhibitor (SNRI)?
| A) | | Duloxetine |
| B) | | Milnacipran |
| C) | | Mirtazapine |
| D) | | Venlafaxine |
ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT
The dual serotonergic and noradrenergic re-uptake
inhibitors (SNRIs) duloxetine, venlafaxine, and milnacipran are widely used in the
treatment of neuropathic pain conditions. Duloxetine is used in painful diabetic
neuropathy, with demonstrated efficacy at 60–120 mg/day. Venlafaxine behaves like a SSRI
at doses of ≤150 mg/day and like an SNRI at doses >150 mg/day; a dose ≥150 mg/day is
often necessary to achieve pain control [76]. Of the three available SNRIs, milnacipran has the greatest affinity for
norepinephrine, duloxetine has the greatest potency in blocking serotonin, and venlafaxine
selectively binds to the serotonin but not the norepinephrine transporter [115].
20 . Which of the following is appropriate for mild pain, according to the WHO analgesic ladder?
| A) | | Weak opioids |
| B) | | Strong opioids |
| C) | | Nonopioid analgesics |
| D) | | None of the above |
USING MULTIMODAL PAIN THERAPY: EXAMPLES FROM THE PROFESSIONAL LITERATURE
