Postoperative Pain Management
Yusuke Mazda, MD PhD
, Sandra Jadin, MD
, James S. Khan, MD MSc FRCPC
Division of Obstetric Anesthesia, Department of Anesthesiology, Saitama Medical Center, Saitama Medical University, Kawagoe,
Department of Anesthesiology and Perioperative Medicine, Queens University, Kingston, Canada;
Department of Anesthesia
and Pain Medicine, University of Toronto, Toronto, Canada
Corresponding Author: Dr. James S. Khan, MD MSc FRCPC:
Submitted: November 6 2020. Accepted: January 18, 2021. Published: March 16, 2021. DOI: 1022374/cjgim.v16iSP1.529
Copyright: Yusuke Mazda et al.
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons
After surgery, over 80% of people experience moderate-to-severe acute pain. Poorly controlled
postoperative pain limits recovery and is associated with detrimental short- and long-term
morbidity. While surgeons have traditionally been responsible for postoperative pain management,
all clinicians providing care for surgical patients have a basic understanding of common
pharmacologic and interventional pain management strategies. In this review, we discuss the
consequences of acute pain, approaches to pain assessment, and an overview of commonly used
therapies to manage postoperative pain.
Après une opération, plus de 80% des gens ressentent des douleurs aiguës modérées à intenses.
Une douleur postopératoire mal maîtrisée limite le rétablissement et est associée à une morbidi
défavorable à court et à long terme. Bien que les chirurgiens soient habituellement responsables
du traitement de la douleur postopératoire, il est impératif que tous les cliniciens qui soignent des
patients ayant subi une intervention chirurgicale aient une connaissance de base des stratégies
pharmacologiques et interventionnelles courantes relatives au traitement de la douleur. Dans cette
revue, nous abordons les conséquences de la douleur aiguë, les approches de l’évaluation de la
douleur et un aperçu des traitements couramment utilisés pour traiter la douleur postopératoire.
Key Points
Acute pain is common after surgery and many patients will suffer from moderate-to-severe
postoperative pain.
Postoperative pain is associated with poor clinical outcomes, patient dissatisfaction, and long-
term morbidities such as chronic post-surgical pain.
Comprehensive pain assessments are needed to plan for the use of analgesic therapies
preoperatively, intraoperatively, and postoperatively.
Multimodal analgesia is the optimal treatment strategy and includes the use of several
different therapies to achieve adequate pain control.
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Postoperative pain is one of the most significant concerns for
patients when undergoing surgery
and is a strong predictor
of whether patients are satisfied with their perioperative care.
Unfortunately, approximately 88% of patients report moderate-to-
severe acute pain after surgery.
Unmanaged postoperative pain
has consequences which include deleterious physiological effects,
increased healthcare utilization, and poor clinical outcomes,
such as acute pain predisposing to the development of chronic
post-surgical pain (CPSP).
While our understanding and
tools to manage pain have improved, inadequately controlled
postoperative pain continues to be an unresolved global health-care
problem. Furthermore, the recent and ongoing opioid epidemic
has increased pressure to reduce opioids during and after surgery
as a strategy to mitigate the rates of persistent opioid use.
such, there is increasing interest to provide multimodal analgesia
and identify novel interventions to improve postoperative pain
management and reduce persistent post-surgical opioid use.
While postoperative pain has traditionally been the
primary responsibility of surgeons, successful management of
postoperative pain requires a multidisciplinary approach that
involves anesthesiologists, internists, perioperative physicians,
and family physicians.
An understanding of postoperative pain
and commonly used interventions are required for effective
management of patients undergoing surgery. This article aims
to provide a basic overview of the principles, approaches, and
strategies to manage acute postoperative pain.
Physiology of Acute Postoperative Pain
Postoperative pain refers to pain immediately after surgery and
can persist for weeks and months. The International Association
for the Study of Pain proposes that the normal healing time
following surgery is approximately 3 months, and any pain
after this period (that did not exist prior to surgery), should be
considered pathologic (i.e., CPSP).
Acute surgical pain is described as nociceptive pain that is
well-localized and characterized as sharp, aching, or throbbing.
It is triggered by the activation of local peripheral nociceptive
fibers, specifically the lightly myelinated A-delta and slow-
conducting unmyelinated C fibers.
These fibers are activated
via thermal, mechanical, and chemical-induced tissue injury.
Surgery results in direct activation of these nociceptive fibers
through mechanical trauma from a surgical incision, manual
handling of tissues, and surgical retraction. As such, acute pain
is influenced by the location of surgery, its extent, and degree
of tissue and neuronal traumatization.
These mechanical
injuries initiate an inflammatory cascade of events that result
in an outpouring of mediators including potassium, adenosine-
triphosphate, sodium, nerve growth factor (NGF), tumor necrosis
factor-alpha (TNF-α), prostaglandins, bradykinins, histamines,
and interleukins
that result in further chemical-induced
activation of local nociceptive fibers.
Nociceptive input from A-delta and C fibers enters the
spinal cord via the dorsal horn and synapses with second-
order neurons at A-delta at Laminae II and V, C and Laminae
II. From here, pain signals cross to ascending spinothalamic
and spinoreticular pathways to ultimately reach higher brain
centers. Spinothalamic tract neurons synapse with third-order
neurons in the thalamus, relaying the signal to the cortex, and
spinoreticular tract neurons synapse in the brainstem with
projections to the thalamus, hypothalamus, and cortex, and
are involved in the emotional and psychological experience of
pain. Given the multiple triggers involved in postoperative pain,
effective pain management strategies aim to address specific
nociceptive triggers (i.e., inflammation from the surgical incision,
neuropathic pain from local nerve injury) and sites (e.g., dorsal
horn where opioids act) along the pain pathways.
Clinical Consequences of Acute Pain
There are several physiological and clinical consequences of
postoperative pain (Table 1).
Pain contributes to increased
heart rate, hypertension, increased myocardial contractility,
and potentially myocardial ischemia.
Pain also alters normal
respiratory function via splinting of the abdominal muscle,
diaphragmatic dysfunction, reduced vital capacity, and inability to
cough, especially for surgeries that require an abdominal incision.
Other physiological effects of postoperative pain include reduced
intestinal motility, altered renal physiology, impaired immune
and coagulation function, muscle weakness, sleep disruption,
and psychological distress.
Furthermore, from a healthcare
resource perspective, acute postoperative pain also results in
prolonged recovery room stay, delayed hospital discharge, and
unanticipated admissions or readmissions after surgery.
Table 1. Consequences of Inadequate Postoperative Pain
Reduce QoL
Impaired sleep
Impaired physical activities, which may delay recovery
Impaired mental status
Develop chronic pain
Increase postoperative readmission
Increase ED visit for refilling pain medications
Increase cost of care
Long-term opioid use
QoL = Quality of Life; ED = Emergency Department.
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Poorly controlled acute pain after surgery has an impact
on a patients well-being long after the immediate postoperative
period. Patients with moderate-to-severe pain (≥4 on a 0–10 scale)
within 4 days after surgery were at increased risk of functional
limitations, poor recovery, and decreased quality of life 6-months
after surgery.
Furthermore, greater acute pain is a predictor of
the development of CPSP.
CPSP has recently been designated
as a separate pain disorder by the International Classification
of Diseases,
and is associated with reduced physical function,
psychological and emotional distress, and poor quality of life.
Assessment of Pain
An accurate assessment of pain is critical to effective pain
management. Pain is a subjective experience and is influenced
by the patients genetics, emotions, mood, and other ongoing
medical issues. It is important that the patients pain is assessed
using validated pain intensity instruments. Pain intensity scales
are often used and include the Numeric Rating Scale (0 to 10 scale
where 0 represents no pain and 10 represents worst imaginable
pain), Verbal Rating Scale (comprises a list of adjectives used
to denote increasing pain intensities), and the Visual Analog
Scale (a 10-cm line anchored by verbal descriptors of “no pain
and “worst imaginable pain” and the patient is asked to mark a
line to indicate pain intensity).
There is insufficient evidence
to recommend a specific pain assessment tool over another in
the postoperative period, although the numerical rating scale
(NRS) is the most commonly used, with satisfactory analgesia
commonly occurring with ≤3 out of 10, and an estimated minimally
important difference of 2 points.
Additionally, the Brief Pain
Inventory (BPI) is a simple and easy tool for assessing pain and
is useful in chronic or cancer pain; however, it is not clinically
feasible to assess acute surgical pain due to pain dynamics
and high frequency for assessments by nurses. Assessing pain
in older adults or those with cognitive impairments presents
greater challenges. Observation scales, such as the Abbey pain
scale, use observed behavior and physiological parameters to
give a numerical pain assessment.
It is imperative that pain is not only evaluated at rest but
also in movement. Movement-evoked pain is often neglected;
however, it is estimated to be 95–226% more intense than pain at
rest and more directly affects post-surgical functional recovery.
A surrogate measure of pain intensity in the postoperative
period is opioid consumption. If opioids are available on an “as
needed” basis and patients have increased pain, their opioid
usage will increase. Some have argued that a composite score of
pain intensities and opioid consumption should be considered
for a more valid assessment of pain.
Additional elements
of a postoperative pain assessment should include the onset
and pattern of pain, location, quality of pain, aggravating and
alleviating factors, previous effective or ineffective therapies, and
effect of pain on sleep, mood, emotions, and physical function.
Overview of Acute Pain Management
Professional association guidelines (American Pain Society
[APS], the American Society of Regional Anesthesia and Pain
Medicine [ASRA], and the American Society of Anesthesiologists
[ASA]) have provided general recommendations for optimal
postoperative pain management.
These recommendations
include preoperative education, accurate pain assessment,
multimodal analgesia, and transitional management (Table 2).
They particularly emphasize the importance of patient education
and reducing opioids after surgery. Of note, positive and goal-
directed patient expectation enhances early recovery from
surgery, and postoperative opioid tapering should be planned by
both hospital specialists and family physicians. Adequate pain
management promotes patient recovery and rehabilitation and
might reduce postoperative adverse events, even healthcare costs
as well.
The goal of postoperative pain management should
be not to eliminate pain (i.e., achieving zero pain). Aiming for
complete pain relief may prove challenging and can lead to
overuse of pain medications. Clinicians should aim to balance
the efficacy and side-effects of pain therapies.
The optimal management of postoperative pain first
begins preoperatively. Identifying those at high risk of acute
postoperative pain allows for early consideration of preventative
analgesics (i.e., preoperative and intraoperative medications
or interventions) (Table 2). Preoperative pain, chronic opioid
use, pain catastrophizing, and type of surgery, specifically
orthopedics, urologic, general surgery, and plastic surgery, are
all risk factors for increased postoperative pain.
younger age, females, preoperative pain, and opioid use, increased
postoperative pain, and psychological factors (i.e., depression,
anxiety, and catastrophizing), appear to be risk factors for CPSP.
Multimodal analgesia is the desired method for postoperative
pain management. This includes combining different analgesic
therapies to provide analgesia while minimizing the side-effect
of each medication.
This approach is recommended both for
patients with prolonged hospital stays postoperatively or day cases
that go home immediately after surgery. Utilizing agents that
target different mechanisms along the pain pathway will allow
for improved analgesia.
In the following section, we outline
commonly used analgesic therapies in the perioperative period. It
is recommended that these options are used in combination and
tailored to the specific patient characteristics such as coexisting
medical conditions as well as institutional resources. Of note,
patients with chronic pain on analgesic medications should
continue the basal analgesia throughout the surgical period
and will require interdisciplinary care (e.g., anesthesiologists
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or acute pain service) to modify the basal therapy in addition
to adding patient-specific analgesic regimens.
Pharmacological Therapies
Acetaminophen is considered one of the cornerstones of
multimodal pain management. It was first discovered in the
19th century,
and since then it has become the most widely
used drug in the world.
While its mechanism of the analgesic
action is not clear, it is believed to exert its action via central
and peripheral cyclooxygenase inhibition, modulation of spinal
serotonin, endocannabinoid activity, and inhibition of nitric
A recent study concluded that scheduled administration
of Acetaminophen had a statistically significant decrease in
pain scores at all time intervals.
It is available in oral, rectal,
and intravenous (IV) forms, with the analgesic effects of rectal
acetaminophen lasting longer.
The oral and rectal routes have
been preferred over IV due to lack of pain during administration.
The IV formulation was approved in Europe in 2002, the United
States in 2011, and in Canada in 2018.
Currently, there is limited
evidence to suggest one formulation is superior to another.
It is important to note that absorption of rectal acetaminophen
can vary with absorption from lipophilic-based suppositories
being more rapid than from water-based formulations.
Table 2. Perioperative Pain Management Considerations and Recommendations
Preoperative evaluation
Identification of risk factors
Consider referral to Acute Pain Service or Transitional Pain Service
Consider regional anesthetic technique (single-shot or continuous catheter) for patients/procedures at high-risk of postoperative pain
Consider neuraxial technique, with possible intrathecal opioids
Intraoperative lidocaine or ketamine infusions
Comprehensive daily pain assessments
Mild pain/Minor surgical procedure
Acetaminophen 500–1000 mg PO every 6 h for 3–5 days
and one of the following
Celecoxib 100–200 PO BID for 3–5 days
Ibuprofen 200–800 mg PO BID every 4 h for 3–5 days
Naproxen 250–500 mg PO BID for 3–5 days
(If cannot take oral medications)
Acetaminophen 1000 mg IV every 6 h (if available) for 3–5 days
Ketorolac 15 mg IV every 8 h for 3 days
In addition to one of the following:
Oxycodone 5–10 mg PO every 4 h as needed
Hydromorphone 1–2 mg PO every 4 h as needed
Morphine 5–15 mg PO every 4 h as needed
Moderate pain/Invasive surgical procedure
Options in order of increasing difficulty in managing pain
1. Standing Acetaminophen and NSAIDs (if possible)
2. Consider Patient Controlled Analgesia
3. Consider postoperative regional anesthetic technique
4. Consider Ketamine infusion
5. Consider Lidocaine infusion
6. Consider Cannabinoids
7. Consider Gabapentinoids
BID = twice a day; NSAID = Nonsteroidal anti-inflammatory drug; PO = oral route.
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The efficacy of perioperative acetaminophen is well-studied.
A Cochrane review reported that with a single oral analgesic
dose of 975 mg to 1 g, the number needed to treat (NNT) to
experience a 50% pain relief over 4 to 6 h after administration
is 3.6 (95% CI 3.4 to 4.0).
Given its high tolerability and low
side-effect potential,
acetaminophen is often used as a first-
line agent. However, the role of acetaminophen as an opioid-
sparing agent is unclear. A recent systemic review of the use of
acetaminophen in patients after major surgery who were also
using patient-controlled analgesia (PCA) indicated a reduction
in morphine consumption of 8.7 mg (95% CI −11.4 to −5.9),
after adjusting for baseline opioid consumption.
Joint practice
guidelines from the APS, ASRA, and ASA recommend the
routine use of acetaminophen postoperatively.
While they
are not clear on whether acetaminophen should be prescribed
as a standing dose versus as-needed dose, many institutional
practices prescribe standing doses during the in-hospital stay
after surgery.
The main concern with acetaminophen is hepatotoxicity
mediated through the accumulation of a highly reactive metabolite
(N-acetyl-p-benzoquinoneimine [NAPQI]); fortunately, it is rare
when given at therapeutic doses (below 4 g/day).
patients at increased risk for toxicity is important to reduce
the dose or avoid acetaminophen all together (e.g., those with
cirrhosis, alcohol use, or on P450 inducers such as carbamazepine,
phenytoin, rifampin).
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Nonsteroidal anti-inflammatory drugs act by inhibiting the
cyclooxygenase (COX) enzyme, which is responsible for the
formation of prostaglandins from arachidonic acid and is involved
in acute inflammatory pain.
COX is found in two isoforms:
COX-1 and COX-2. COX-1 is constantly expressed and plays
an essential role in the maintenance of gastrointestinal mucosa,
platelet function, and renal perfusion, whereas COX-2 is induced
by inflammation.
All NSAIDs bind to both COX enzymes,
with non-selective NSAIDs (i.e., ibuprofen, naproxen, ketorolac)
having a greater affinity for the COX-1 enzyme, whereas COX-2
selective NSAIDs (i.e., celecoxib, rofecoxib) have greater affinities
for the COX-2 enzyme (5- to 50-fold greater).
Oral NSAIDs have been shown to be effective in managing
acute postoperative pain. The NNT for a single oral dose of
common NSAIDs (to produce at least 50% maximum pain
relief over 4–6 h) are quite low (i.e., ibuprofen 200 mg: NNT 2.1,
diclofenac 50 mg: NNT 2.1).
Both perioperative NSAIDs and
COX-2 inhibitors appear to reduce IV morphine consumption
by 10 mg of morphine.
Perioperative NSAIDs have also been
shown to reduce postoperative nausea, vomiting, sedation,
and improve patient satisfaction.
Further, there is ample
data to suggest that NSAIDs are more effective analgesics than
and that combination is more effective than
a single agent alone.
There is inconclusive evidence with regard to clinically
significant side effects of perioperative use of NSAIDs.
In addition to well-known side-effects of gastric bleeding,
thromboembolic events, and renal dysfunction, two specific
adverse effects exist within the perioperative period, anastomotic
leaks after gastrointestinal surgeries and impaired bone healing
after orthopedic surgeries. A meta-analysis (16 studies, 15,242
fractures) evaluating the latter complication demonstrated an
increased risk (OR 2.07, 95% CI 1.19 to 3.61) of prolonged
or impaired bone healing with NSAIDs use after orthopedic
procedures (adult and pediatric).
However, the effect was
not identified for low-dose NSAIDs (diclofenac <125 mg/
day, ketorolac 120 mg/day) taken for less than 2 weeks, which
has been confirmed in additional studies.
spine surgeons have erred on the side of caution and prefer to
avoid NSAIDs postoperatively.
Additionally, within patients
undergoing colorectal surgery, a meta-analysis (24 studies, n
= 31,877) showed an increased risk for anastomotic leaks (OR
1.73, 95% CI 1.31 to 2.29) with the use of NSAIDs.
there are conflicting data to definitively demonstrate an effect
on anastomotic leaks, NSAIDs after gastrointestinal surgeries
have been shown to improve the return of bowel function and
Joint guidelines from the APS, ASRA, and ASA state
that there is insufficient evidence to recommend against the
use of NSAIDs in orthopedic surgeries, spinal fusions, and
colorectal surgery.
Nonsteroidal anti-inflammatory drugs are a useful adjunct to
acute pain management after surgery and should be considered
for all patients after surgery, except for patient populations at
high risk of adverse events (e.g., elderly, renal dysfunction,
gastric ulcers, significant bleeding). COX-2 selective inhibitors
have significantly lower upper gastrointestinal complications,
no antiplatelet effects, and possibly lower risk of renal effects,
allowing it to be considered particularly in elderly patients.
Generally, if NSAIDs and COX-2 inhibitors are used, they should
be given in their lowest effective dose for only a brief period
after surgery (3–7 days).
Gabapentinoids, such as pregabalin and gabapentin, are anti-
convulsants that are also a class of analgesic medications. The
primary mode of action is inhibition of voltage-gated α2δ
calcium channels leading to inhibition of neurotransmitter
While prior reviews have suggested that gabapentinoids
reduce postoperative pain and opioid consumption,
a recently
published meta-analysis (281 trials, n = 24,682) showed no
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clinically significant effect on postoperative pain control.
While gabapentinoids were associated with lower pain on
a 100-point scale, the difference was not large enough to be
considered clinically significant. Further, it is important to
consider the increased risk of adverse events compared to the
minimal opioid-sparing effects.
Given an increased number
of reported side effects such as visual disturbances and dizziness,
the usefulness of these agents in the perioperative setting has
been recently questioned.
Ketamine is a dissociative anesthetic and is often used during
general anesthesia and for procedural sedation. It produces rapid
sedation and analgesia that is mediated through antagonism of the
N-methyl-D-aspartate receptors (NMDA).
A 2020 systematic
review of randomized controlled trials (RCT) indicated that
when ketamine was given as an adjuvant to general anesthesia,
there were significant reductions in pain intensity up to 24 h
after surgery and reduced opioid consumption for up to 12 h
These findings were generally consistent with
a prior 2018 Cochrane review, except that the opioid reduction
effect was seen up to 48 h.
Ketamine has been demonstrated to be an effective agent
for postoperative pain after a number of surgical procedures
including abdominal surgery, orthopedic, spinal, otolaryngologic,
and gynecological procedures.
Ketamine reduces postoperative
pain scores at rest up to 72 h after surgery (weighted mean
difference [WMD] −1.3, 95% CI −2.4 to −0.2).
Further, ketamine
infusions reduced postoperative opioid consumption up to 48
h after surgery (WMD [cumulative morphine consumption]
−12.7 mg, 95% CI −18.9 to −6.6) and reduced postoperative
nausea and vomiting, which may be related to its opioid-reducing
Additionally, intravenous ketamine infusions can
assist in reducing postoperative pain in opioid-tolerant patients
and those with chronic pain undergoing surgery.
In a prior
systematic review, ketamine has been shown to reduce CPSP
at the 3rd month.
However, ketamine can alter blood pressure, heart rate, and
mental status, so administration should be done carefully when
performed outside a monitored setting (e.g., surgical ward).
Ketamine is associated with psychotomimetic effects (e.g.,
hallucinations, nightmares), however, when given intraoperatively,
there was no significant increase in these side-effects, particularly
if a benzodiazepine is administered.
Typical infusion regimens
range from 0.02 to 0.1 mg/kg/h (any dosage below <0.25 mg/kg/h
is considered sub-anesthetic), and at these dosages, side-effects
are uncommon.
Longer infusions (24–72 h) are safe and
show increased benefit over shorter infusions. Infusions should
be typically administered in collaboration with the hospital Pain
Service or Anesthesia colleagues and should be considered in
patients with challenging to manage postoperative pain refractory
to opioid management, after major noncardiac surgery (i.e.,
spine, thoracotomies), and those with a history of chronic pain
or opioid tolerance. Ketamine may not be appropriate for day
surgical cases and small procedures not associated with intense
postoperative pain. More studies will certainly be required to
clearly define the role of ketamine for postoperative analgesia.
Intravenous Lidocaine Infusions
Lidocaine is an amide local anesthetic that provides analgesia
through antagonism of voltage-gated sodium channels and appears
to have anti-inflammatory and anti-hyperalgesic properties.
While lidocaine is most often used for local or regional anesthesia,
there has been increasing use of intravenous lidocaine in recent
years. It has been used to treat chronic pain disorders in an
outpatient setting for decades.
Enhanced Recovery After Surgery
(ERAS) guidelines adopted intraoperative intravenous lidocaine
in bowel surgery given data that it improves postoperative pain,
opioid consumption, the return of bowel function, and length
of hospital stay (current level of recommendation: strong).
recent Cochrane review of RCTs confirmed an effect on reducing
pain scores up to 24 h after surgery as well as a significant
reduction in risk of ileus, time to first defecation, postoperative
nausea, and opioid consumption (mean difference [MD] 4.52
mg morphine equivalents, 95% CI −6.25 to −2.79).
infusions typically start intraoperatively and many centers have
migrated to using postoperative infusions for acute pain.
Despite the widespread use of lidocaine infusions in clinical
practice, during and after surgery, there is little guidance on
specific indications, ideal infusion regimen (dose and duration),
and what monitoring should be performed. Most benefit has been
documented within gastrointestinal surgeries—however, most
studies have been within this surgical population. In breast cancer
surgery, an intraoperative lidocaine infusion appears to reduce
the development of CPSP.
Postoperative lidocaine infusions
should be considered in patients with refractory acute pain not
responsive to opioid therapy, abdominal surgeries, and history of
chronic pain. Typical lidocaine infusion dosages include a bolus
of 1–1.5 mg/kg followed by a 1–3 mg/kg/h infusion; bolus dose
can be omitted if the infusion is expected to continue for hours to
Monitoring for possible local anesthetic toxicity should be
performed, however, at the specified infusion regimens, toxicity
is rare.
Toxicity ranges from mild-to-severe adverse effects in
a dose-dependent relationship. Mild symptoms include perioral
paraesthesia, visual disturbances, tinnitus, sedation, with severe
toxicity resulting in cardiovascular collapse and seizures. Thus,
monitoring for mild symptoms with cessation of an infusion
can prevent progression to severe toxicity. Some institutions
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measure plasma lidocaine concentrations (toxicity occurring
above 5 µg/mL),
as an extra safety mechanism, although this
is not done routinely.
Toxicity is treated with lipid emulsion
(e.g., Intralipid
). The use of Intralipid (lipid emulsion) as a
treatment of local anesthetic toxicity (LAST) has become a
standard of care. It is a lipid emulsion that acts as a lipid sink to
draw the hydrophobic local anesthetics out of the tissues. The
American Society of Regional Anesthesia has published specific
recommendations and a checklist for the treatment of LAST.
Cannabinoids are substances that act on the cannabinoid CB1
and CB2 receptors. CB1 receptors are found predominately in the
brain and spinal cord (along the pain pathways), whereas CB2
receptors are primarily found on immune cells.
Two categories
of cannabinoids exist, cannabis-derived pharmaceuticals (i.e.,
dronabinol and nabilone) and botanical-derived extracts. Analgesic
efficacy of cannabinoids has been primarily demonstrated in
chronic pain patients,
with little literature on perioperative
use. A recent systematic review of RCTs (924 patients) and
observational studies (4259 patients) on the use of cannabinoids
for acute pain in the perioperative period indicated no significant
reduction in opioid consumption but a significant increase in
pain at 12 h after surgery and increased odds of hypotension.
Considering the current evidence base, there are no strong
indications to use cannabis in the perioperative period.
Opioids are considered as a central component of postoperative
pain management (Figure 1). Opioids exert their action by
binding to opioid receptors (e.g., mu, delta, and kappa), which
are located on the central and peripheral nervous system. The mu
receptor is primarily involved in providing analgesia; however,
mu receptors are also expressed on the gastrointestinal tract and
Figure 1. Opioids as a central component of postoperative pain management.
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may be involved in causing opioid-induced nausea, vomiting,
and constipation. Opioids can be administered via oral, rectal,
sublingual, transdermal, subcutaneous, intramuscular, intravenous,
or neuraxial routes. The most commonly used drugs after
surgery for in-patient acute pain are oxycodone, morphine, and
hydromorphone in Canada,
although the most frequently
prescribed opioids in the US was oxycodone with acetaminophen
and hydrocodone with acetaminophen, and those in the UK was
morphine and codeine with acetaminophen.
After a major
surgery, opioids are typically delivered via patient-controlled
analgesia (IV PCA), which allows patients to control their opioid
administration while reducing the risk of overdose and can
also reduce nursing workloads,
facilitate early ambulation,
reduce respiratory complications, and provide higher patient
Although opioids have a diverse range of side-effects (Table3),
life-threatening adverse events, such as respiratory depression,
are rare and typically happen within 24 h after surgery under
intravenous patient-controlled or neuraxial analgesia.
systematic review of observational studies reported the incidence
of postoperative opioid-induced respiratory depression of 5 in
Also, those with pre-existing cardiac disease, pulmonary
disease, and obstructive sleep apnea are at increased risk of
opioid-induced respiratory depression.
Surgery is a period where opioid-naïve patients become
exposed to opioids. Unfortunately, up to 6.5% of patients after
minor and major surgery develop new persistent opioid use.
Tobacco use, alcohol and substance abuse disorders, mood
disorders, anxiety, and preoperative pain are risk factors for
persistent use. Opioid prescribing after surgery, and particularly
at discharge appears to be an important factor—45% of patients
who do not take opioids on their last day in the hospital after
surgery are prescribed opioids upon discharge.
patients only used 27% of the opioids prescribed to them
after surgery and prescription size was the strongest predictor
of long-term opioid use.
A multidisciplinary expert panel
(composed of surgeons, pain specialists, pharmacists, patients)
at John Hopkins provided consensus recommendations on the
appropriate opioid prescribing after different surgical procedures.
Recommendations for prescribing for most surgeries include
0 to 15 tablets of oxycodone 5 mg, with only certain surgeries
(thoracic, orthopedic, open gynecological surgeries) allowing up to
20 tablets. A Canadian consensus statement on recommendations
for opioid prescribing after surgery has also been published and
includes a number of recommendations including (in part)
patient education about appropriate expectations and non-
opioid analgesia use, identification of risk factors, basing opioid
prescription on functional recovery after surgery, prescription
having an expiry date of 30 days from discharge, and if a refill
is needed, only providing a 14-day refill.
Interventional Pain Procedures
Regional anesthesia involves using local anesthetics to produce a
conduction block at specific neuronal tissues. Patients may receive
a regional anesthetic as their primary form of anesthesia during
surgery or to assist with postoperative pain. These procedures
are typically performed under ultrasound-guidance, which may
reduce complications compared to traditional landmark-based
Literature on the efficacy of regional anesthesia
after surgery varies on the type of procedure and specific
technique, but overall, these procedures have been shown to
result in improved postoperative analgesia and reduced opioid
A large number of regional techniques are
used perioperatively and include epidural anesthesia/analgesia
(cesarean sections and midline laparotomies), brachial plexus
blocks (i.e., interscalene, supraclavicular, infraclavicular, axillary
brachial plexus blocks for upper extremity procedures), fascial
iliac plane block (for hip surgery), adductor canal block (used
in knee surgeries), and erector spinae block (for mastectomy or
truncal surgeries).
The length of the effect depends on the type
of local anesthetic and whether the procedure is a “single-shot
(12 to 24 h) or includes placement of a catheter, which allows
for continuous infusion of local anesthesia (several days after
Further, the combination of multiple regional
blocks appears to provide superior analgesia compared to
Table 3. Common Opioid-Related Side-Effects
Common Occasional Rare
Delayed gastric
Biliary colic
Mood disturbance
Cough reflex
Dry mouth
Respiratory depression
Noncardiac pulmonary
Miosis Pruritis
Muscle rigidity
Physical dependence
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single-injection techniques.
Furthermore, for certain surgical
populations, such as hip fracture patients, early regional techniques
should be considered as they will typically be in pain prior to
their surgical procedure. A study in patients admitted with hip
fractures indicated that a preoperative fascia iliaca nerve block
resulted in lower preoperative opioid consumption, lower pain
intensities, and earlier discharge.
Several factors discourage the use of regional anesthesia,
such as lack of clinical experiences or resources and, access to
an ultrasound machine which is considered standard-of-care
in performing regional anesthesia. Of note, regional anesthesia
technique and timing (i.e., when to perform, if a catheter can
be placed, when to remove catheter) is also dependent if the
patient is on anticoagulation or antiplatelet therapy or has a
bleeding disorder.
In general, peripheral nerve blocks may be
considered in patients with anticoagulation/antiplatelet therapy,
whereas neuraxial techniques are contraindicated (i.e., due to
risk of epidural hematomas causing spinal cord or nerve root
Patients with Chronic Pain Presenting for Surgery
Patients with a history of chronic pain are more likely to experience
moderate-to-severe pain after surgery.
These patients may
also be maintained on chronic opioids which presents further
challenges within the perioperative period. These patients are
not only at higher risk of more severe pain and greater opioid use
after surgery, but epidemiological studies also indicate that they
are at higher risk of poor postoperative outcomes—in a cohort
of 200,005 patients undergoing elective surgery, preoperative
opioid use was associated with a longer hospital stay, higher
rate of readmission, and increased healthcare expenditures.
Multidisciplinary perioperative care models such as the
Transitional Pain Service have been developed to manage
these high-risk patients. These programs typically evaluate
patients prior to surgery, mitigate exacerbating factors, provide
interdisciplinary care including behavioral management strategies,
and support care after discharge.
In general, patients on
long-term non-opioid analgesics should have their medications
continued in the perioperative period, with some exceptions
such as NSAIDs in surgery at high-risk of bleeding. Further,
patients on chronic opioids should be continued on their home
doses in the perioperative period, while anticipating greater
opioid consumption after surgery (up to three times greater)
compared to opioid-naïve patients.
Long-acting opioid
formulations such as buprenorphine should also be continued
perioperatively, as suggested by Canadian expert consensus.
Opioid-tolerant patients should be maximized on non-opioid
adjuncts, interventional regional techniques, and particularly
ketamine infusions, which has been shown to reduce pain
intensities and opioid consumption in those with chronic opioid
In challenging cases, opioid rotation (changing from one
opioid to another) can potentially be helpful in the postoperative
period, which takes advantage of the incomplete cross-tolerance
of opioids.
High-risk patients such as those with a preoperative
history of chronic pain and those maintained on chronic opioids
should likely be followed after hospital discharge for titration
back to baseline analgesic and opioid dosages.
Postoperative pain is an important consideration in a patient’s
perioperative care. Unmanaged pain may contribute to poor
postoperative clinical outcomes, including CPSP which is
analogous to a functional disability associated with increased
healthcare expenditures. Optimal management of postoperative
pain includes multimodal and interdisciplinary approaches
with the utilization of effective therapies in the preoperative,
intraoperative, and postoperative periods.
1. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience:
Results from a national survey suggest postoperative pain continues
to be undermanaged. Anesth Analg. 2003;97(2):534–40. http://dx.doi.
2. Myles PS, Williams DL, Hendrata M, Anderson H, Weeks AM. Patient
satisfaction after anaesthesia and surgery: Results of a prospective survey of
10,811 patients. Br J Anaesth. 2000;84(1):6–10.
3. Institute of Medicine. Relieving pain in America: A blueprint for
transforming prevention, care, education, and research. Washington, DC:
National Academies Press; 2011.
4. Joshi GP, Ogunnaike BO. Consequences of inadequate postoperative pain
relief and chronic persistent postoperative pain. Anesthesiol Clin North Am.
5. Coley KC, Williams BA, DaPos SV, Chen C, Smith RB. Retrospective
evaluation of unanticipated admissions and readmissions after same
day surgery and associated costs. J Clin Anesth. 2002;14(5):349–53.
6. Small C, Laycock H. Acute postoperative pain management. Br J Surg.
7. Schug SA, Lavand’homme P, Barke A, Korwisi B, Reif W, Treede RD, et al.
The IASP classification of chronic pain for ICD-11: Chronic postsurgical or
posttraumatic pain. Pain. 2019;160(1):45–52.
8. Weiss T, Straube T, Boettcher J, Hecht H, Spohn D, Miltner WHR.
Brain activation upon selective stimulation of cutaneous C- and Adelta-
fibers. Neuroimage. 2008;41(4):1372–81.
9. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: Risk factors
and prevention. Lancet. 2006;367:1618–25.
10. Zubrzycki M, Liebold A, Skrabal C, Reinelt H, Ziegler M, Perdas E, et al.
Assessment and pathophysiology of pain in cardiac surgery. J Pain Res.
11. Feizerfan A, Sheh G. Transition from acute to chronic pain. Continuing
Educ Anaesth Crit Care Pain. 2015;15(2):98–102.
Canadian Journal of General Internal Medicine
Volume 16, Special Issue 1, 2021 13
Mazda et al.
CJGIM_1_2021_176993.indd 13CJGIM_1_2021_176993.indd 13 3/22/21 6:28 PM3/22/21 6:28 PM
12. Gold M, Gebhart G. Peripheral pain mechanisms and nociceptor
sensitization. In: Fishman S, Ballantyne JC, Rathmell JP, editors. Bonicas pain
management. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.
p. 25–34.
13. Baratta JL, Schwenk ES, Viscusi ER. Clinical consequences of inadequate pain
relief: Barriers to optimal pain management. Plast Reconstr Surg. 2014;134
(4 Suppl 2):15S–21S.
14. Pavlin DJ, Chen C, Penaloza DA, Buckley FP. A survey of pain and
other symptoms that affect the recovery process after discharge from an
ambulatory surgery unit. J Clin Anesth. 2004;16(3):200–6. http://dx.doi.
15. Fortier J, Chung F, Su J. Unanticipated admission after ambulatory
surgery—A prospective study. Can J Anaesth 1998;45(7):612–19. http://
16. Pavlin DJ, Rapp SE, Polissar NL, Malmgren JA, Koerschgen M, Keyes
H. Factors affecting discharge time in adult outpatients. Anesth Analg.
17. Peters ML, Sommer M, de Rijke JM, Kessels F, Heineman E, Patijn J, et al.
Somatic and psychologic predictors of long-term unfavorable outcome
after surgical intervention. Ann Surg. 2007;245(3):487–94. http://dx.doi.
18. Gilron I, Vandenkerkhof E, Katz J, Kehlet HM, Carley M. Evaluating the
association between acute and chronic pain after surgery: Impact of pain
measurement methods. Clin J Pain. 2017;33(7):588–94. http://dx.doi.
19. Bruce J, Quinlan J. Chronic post surgical pain. Rev Pain. 2011;5(3):23–9.
20. Khan JS, Shah R, Gilron I. Outcomes in pain clinical research: What really
matters for patients? Curr Anesthesiol Rep. 2019;9(4):414–21. http://dx.doi.
21. Abbey J, Piller N. De Bellis A, Esterman A, Parker D, Files L, et al. The
Abbey pain scale: A 1-minute numerical indicator for people with end-stage
dementia. Int J Palliat Nurs. 2004;10(1):6–13.
22. Srikandarajah S, Gilron I. Systematic review of movement-evoked pain versus
pain at rest in postsurgical clinical trials and meta-analyses: A fundamental
distinction requiring standardized measurement. Pain. 2011;152(8):1734–9.
23. Jensen MP, Castarlenas E, Tomé-Pires C, de la Vega R, Sánchez-Rodríguez
E, Miró J. The number of rating needed for valid pain assessment in clinical
trials: Replication and extension. Pain Med. 2015;16(9):1764–72. http://
24. Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S,
Brennan T, et al. Management of postoperative pain: A clinical practice
guideline from the American Pain Society, the American Society of
Regional Anesthesia and Pain Medicine, and the Americas Society of
Anesthesiologists’ committee on regional anesthesia, executive committee,
and administrative council. J Pain. 2016;17(2):131–57. http://dx.doi.
25. Gan TJ. Poorly controlled postoperative pain: Prevalence, consequences
and prevention. J Pain Res. 2017;10:2287–98.
26. Sommer M, de Rijke JM, van Kleef M, Kessels AG, Peters ML, Geurts JW,
et al. Predictors of acute postoperative pain after elective surgery. Clin J Pain.
27. Chung F, Ritchie E, Su J. Postoperative pain in ambulatory
surgery. Anesth Analg. 1997;85(4):808–16. http://dx.doi.
28. Lau H, Patil NG. Acute pain after endoscopic totally extraperitoneal (TEP)
inguinal hernioplasty: Multivariate analysis of predictive factors. Surg
Endosc. 2004;18(1):92–6.
29. Cepeda MS, Carr DB. Women experience more pain and require more
morphine than men to achieve a similar degree of analgesia. Anesth Analg.
30. Schug SA, Bruce J. Risk stratification for the development of chronic
postsurgical pain. Pain Rep. 2017;2(6):e627.
31. Garimella V, Cellini C. Postoperative pain control. Clin Colon Rectal Surg.
32. Von Mering J. Beitrage zur Kenntniss der Antipyretica. Ther Monatsch.
33. Brune K, Renner B, Tiegs G. Acetaminophen/paracetamol: A history of
errors, failures and false decisions. Eur J Pain. 2015;19(7):953–65. http://
34. Smith HS. Perioperative intravenous acetaminophen and NSAIDs. Pain Med.
35. Poljak D, Chappele J. The effect of a scheduled regimen of acetaminophen
and ibuprofen on opioid use following caesarean delivery. J Perinat Med.
36. Power I. Recent advances in postoperative pain therapy. Br J Anaesth.
37. Haddadi S, Marzban S, Karami MS, Heidarzadeh A, Parvizi A, Nabi BN.
Comparing the duration of the analgesic effects of intravenous and rectal
acetaminophen following tonsillectomy in children. Anesth Pain Med.
38. Viitanen H, Tuominen N, Vääräniemi H, Nikanne E, Annila P. Analgesic
efficacy of rectal acetaminophen and ibuprofen alone or in combination for
paediatric day-case adenoidectomy. Br J Anaesth. 2003;91(3):363–7. http://
39. Pasero C, Stannard D. The role of intravenous acetaminophen in acute pain
management: A case-illustrated review. Pain Manag Nurs. 2012;13(2):107–24.
40. Kendall MC, Hickman SR. Possible confounders in study of oral versus i.v.
acetaminophen for postoperative pain control. Am J Health Syst Pharm.
41. Jibril F, Sharaby S, Mohamed A, Wilby KJ. Intravenous versus oral
acetaminophen for pain: Systematic review of current evidence to support
clinical decision-making. Can J Hosp Pharm. 2015;68(3):238–47. http://
42. Kahela P, Laine E, Anttila M. A comparison of the bioavailability of
paracetamol from a fatty and a hydrous suppository case and the effect of
storage on the absorption in man. Drug Dev Indust Pharm. 1987;13:213–24.
43. Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol
(acetaminophen) for postoperative pain in adults. Cochrane Database
Syst Rev. 2008;2008(4):CD004602.
44. Moore RA, Derry S, Aldington D, Wiffen PJ. Single dose oral analgesics
for acute post-operative pain in adults—An overview of Cochrane reviews.
Cochrane Database Syst Rev. 2015;2015(9):CD008659. http://dx.doi.
45. Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol
and selective and non-selective non-steroidal anti-inflammatory drugs for the
reduction in morphine-related side-effects after major surgery: A systematic
review. Br J Anaesth. 2011;106(3):292–7.
46. Jamjittrong S, Matsuda A, Matsumoto S, Kamonvarapitak T, Sakurazawa N,
Kawano Y, et al. Postoperative non‐steroidal anti‐inflammatory drugs and
anastomotic leakage after gastrointestinal anastomoses: Systematic review
and meta‐analysis. Ann Gastroenterol Surg. 2019;4(1):64–75. http://dx.doi.
47. Abramson SB, Weissmann G. The mechanisms of action of nonsteroidal
anti-inflammatory drugs. Arthritis Rheum. 1989;32(1):1–9. http://dx.doi.
48. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR.
Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-
oxygenase-2 are associated with human gastrointestinal toxicity: A full in
vitro analysis. Proc Natl Acad Sci U S A. 1999;96(13):7563–8. http://dx.doi.
Canadian Journal of General Internal Medicine
14 Volume 16, Special Issue 1, 2021
Perioperative Medicine Special Issue
CJGIM_1_2021_176993.indd 14CJGIM_1_2021_176993.indd 14 3/22/21 6:28 PM3/22/21 6:28 PM
49. Mathiesen O, Wetterslev J, Kontinen VK, Pommergaard HC, Nikolajsen L,
Rosenberg J, et al. Adverse effects of perioperative paracetamol, NSAIDs,
glucocorticoids, gabapentinoids and their combinations: A topical review.
Acta Anaesthesiol Scand. 2014;58(10):1182–98.
50. Khan JS, Margarido C, Devereaux PJ, Clarke H, McLellan A, Choi S.
Preoperative celecoxib in noncardiac surgery: A systematic review and meta-
analysis of randomised controlled trials. Eur J Anaesthesiol. 2016;33(3):204–
51. Gupta A, Bah M. NSAIDs in the treatment of postoperative pain. Curr Pain
Headache Rep. 2016;20(11):62.
52. Rana MV, Desai R, Tran L, Davis D. Perioperative pain control in the
ambulatory setting. Curr Pain Headache Rep. 2016;20(3):18. http://dx.doi.
53. Martinez V, Beloeil H, Marret E, Fletcher D, Ravaud P, Trinquart L. Non-
opioid analgesics in adults after major surgery: Systematic review with
network meta-analysis of randomized trials. Br J Anaesth. 2017;118(1):22–31.
54. Wheatley BM, Nappo KE, Christensen DL, Holman AM, Brooks DI, Potter
BK. Effect of NSAIDs on bone healing rates: A meta-analysis. J Am Orthop
Surg. 2019;27(7):e330–6.
55. Fader L, Whitaker J, Lopez M, Vivace B, Parra M, Carlson J, et al.
Tibia fractures and NSAIDs. Does it make a difference? A multicenter
retrospective study. Injury. 2018;49(120):2290–4.
56. Hassan MK, Karlock LG. The effect of post-operative NSAID administration
on bone healing after elective foot and ankle surgery. Foot Ankle Surg.
57. Clarke HA, Manno V, Pearsall EA, Goel A, Feinberg A, Weinrib A, et al.
Consensus statement for the prescription of pain medication at discharge
after elective adult surgery. Can J Pain. 2020;4(1):67–85.
58. Li Q, Zhang Z, Cai Z. High-dose ketorolac affects adult spine fusion: A meta-
analysis of the effect of perioperative nonsteroidal anti-inflammatory drugs
on spinal fusion. Spine (Phila Pa 1976). 2011;36(7):E461–8. http://dx.doi.
59. American Society of Anesthesiologists Task Force on Acute Pain
Management. Practice guidelines for acute pain management in the
perioperative setting: An updated report by the American Society of
Anesthesiologists Task Force on Acute Pain Management. Anesthesiology.
60. Chapman SJ, Garner JJ, Drake TM, Aldaffaa M, Jayne DG. Systematic review
and meta-analysis of nonsteroidal anti-inflammatory drugs to improve GI
recovery after colorectal surgery. Dis Colon Rectum. 2019;62(2):248–56.
61. Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of
gastrointestinal adverse effects between cyclooxygenase-2 inhibitors
and non-selective, non-steroidal anti-inflammatory drugs plus proton
pump inhibitors: A systematic review and meta-analysis. J Gastroenterol.
62. Munsterhjelm E, Niemi TT, Ylikorkala O, Neuvonen PJ, Rosenberg PH.
Influence on platelet aggregation of i.v. parecoxib and acetaminophen
in healthy volunteers. Br J Anaesth. 2006;97(2):226–31. http://dx.doi.
63. Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors
on renal and arrhythmia events: Meta analysis of randomized trials. JAMA.
64. Hallingbye T, Martin J, Viscomi C. Acute postoperative pain management in
the older patient. Aging Health. 2011;7(6):813–28.
65. Verret M, Lauzier F, Zarychanski R, Perron C, Savard X, Pinard AM, et al.
Perioperative use of gabapentinoids for the management of postoperative
acute pain: A systematic review and meta-analysis. Anesthesiology.
66. Pavy TJG, Paech MJ, Evans SF. The effect of intravenous ketorolac on
opioid requirement and pain after cesarean delivery. Anesth Analg.
67. Bell S, Rennie T, Marwick CA, Davey P. Effects of peri-operative
nonsteroidal anti-inflammatory drugs on post-operative kidney function
for adults with normal kidney function. Cochrane Database Syst Rev.
68. Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients
benefit from perioperative gabapentin/pregabalin? A systematic review
of efficacy and safety. Anesth Analg. 2007;104(6):1545–56. http://dx.doi.
69. Málek J, Ševčík P, Bejšovec D, Fricová J, Gabrhelík T, Krikava I, et
al. Postoperative pain management. Anesteziol Neodkladna Pece.
70. Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception:
Evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp
Ther. 1992;260(3):1209–13.
71. Wang X, Lin C, Lan L, Liu J. Perioperative intravenous S-ketamine for acute
postoperative pain in adults: A systematic review and meta-analysis. J Clin
Anesth. 2020;68:110071.
72. Brinck EC, Tiippana E, Heesen M, Bell RF, Straube S, Moore RA, et al.
Perioperative intravenous ketamine for acute postoperative pain in adults.
Cochrane Database Syst Rev. 2018;12(12):CD012033. http://dx.doi.
73. Radvansky BM, Shah K, Parikh A, Sifonios AN, Le V, Eloy JD. Role of
ketamine in acute postoperative pain management: A narrative review.
Biomed Res Int. 2015;2015:749837.
74. Wang L, Johnston B, Kaushal A, Cheng D, Zhu F, Martin J. Ketamine
added to morphine or hydromorphone patient-controlled analgesia for
acute postoperative pain in adults: A systematic review and meta-analysis
of randomized trials. Can J Anaesth. 2016;63(3):311–25. http://dx.doi.
75. Kator S, Correll DJ, Ou JY, Levinson R, Noronha GN, Adams CD. Assessment
of low-dose i.v. ketamine infusions for adjunctive analgesia. Am J Health Syst
Pharm. 2016;73(5 Suppl 1):S22–9.
76. Moitra VK, Patel MK, Darrah D, Moitra A, Wunsch H. Low-dose ketamine
in chronic critical illness. J Intensive Care Med. 2016;31(3):216–20. http://
77. Reade MC, Finfer S. Sedation and delirium in the intensive care unit. N Engl
J Med. 2014;370(5):444–54.
78. Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain
relief in patients receiving intravenous opioids for acute pain in the emergency
department: Results of a randomized, double-blind, clinical trial. Acad Emerg
Med. 2014;21(11):1193–202.
79. Urban MK, Ya Deau JT, Wukovits B, Lipnitcky JY. Ketamine as an adjunct
to postoperative pain management in opioid tolerant patients after spinal
fusions: A prospective randomized trial. HSS J. 2008;4(1):62–5. http://dx.doi.
80. Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze
S, et al. Consensus guidelines on the use of intravenous ketamine infusions
for acute pain management from the American Society of Regional
Anesthesia and Pain Medicine, the American Academy of Pain Medicine,
and the American Society of Anesthesiologists. Reg Anesth Pain Med.
81. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy
for the prevention of chronic pain after surgery in adults. Cochrane Database
Syst Rev. 2013;2013(7):CD008307.
82. Sveticic G, Eichenberger U, Curatolo M. Safety of mixture of morphine
with ketamine for postoperative patient-controlled analgesia: An audit with
1026 patients. Acta Anaesthesiol Scand. 2005;49(6):870–5. http://dx.doi.
83. Brown K, Tucker C. Ketamine for acute pain management and sedation. Crit
Care Nurse. 2020;40(5):e26–32.
Canadian Journal of General Internal Medicine
Volume 16, Special Issue 1, 2021 15
Mazda et al.
CJGIM_1_2021_176993.indd 15CJGIM_1_2021_176993.indd 15 3/22/21 6:28 PM3/22/21 6:28 PM
84. Rakic, AM, Golembiewski J. Low-dose ketamine infusion for postoperative
pain management. J Perianesth Nurs. 2009;24(4):254–7. http://dx.doi.
85. Weinbroum AA. A single small dose of postoperative ketamine provides
rapid and sustained improvement in morphine analgesia in the presence of
morphine-resistant pain. Anesth Analg. 2003;96(3):789–95. http://dx.doi.
86. Eipe N, Gupta S, Penning J. Intravenous lidocaine for acute pain: An
evidence-based clinical update. BJA Educ. 2016;16(9):292–8. http://dx.doi.
87. van der Wal SE, van den Heuvel SAS, Radema SA, van Berkum BFM,
Vaneker M, Steegers MAH, et al. The in vitro mechanisms and in vivo
efficacy of intravenous lidocaine on the neuroinflammatory response
in acute and chronic pain. Eur J Pain. 2016;20(5):655–74. http://dx.doi.
88. Gordon RA. Intravenous novocaine for analgesia in burns. Can Med Assoc
J. 1943;49(6):478–81.
89. van Zundert A, Helmstädter A, Goerig M, Mortier E. Centennial of
intravenous regional anesthesia. Bier’s block (1908–2008). Reg Anesth Pain
Med. 2008;33(5):483–9.
90. Gustafsson UO, Scott MJ, Hubner M, Nygren J, Demartines N, Francis
N, et al. Guidelines for perioperative care in elective colorectal surgery:
Enhanced Recovery After Surgery (ERAS®) society recommendations:
2018. World J Surg. 2019;43(3):659–95.
91. Weibel S, Jelting Y, Pace NL, Helf A, Eberhart LH, Hahnenkamp K,
et al. Continuous intravenous perioperative lidocaine infusion for
postoperative pain and recovery in adults. Cochrane Database Syst Rev.
92. Meaney ED, Reid L, Srivastava D. A survey on the use of intravenous
lidocaine infusion for acute pain in Scottish hospitals. Br J Pain.
93. Bailey M, Corcoran T, Schug S, Toner A. Perioperative lidocaine infusions
for the prevention of chronic postsurgical pain: A systematic review and
meta-analysis of efficacy and safety. Pain. 2018;159(9):1696–704. http://
94. Khan JS, Hodgson N, Choi S, Reid S, Paul JE, Hong NJL, et al. Perioperative
pregabalin and intraoperative lidocaine infusion to reduce persistent
neuropathic pain after breast cancer surgery: A multicenter, factorial,
randomized, controlled pilot trial. J Pain. 2019;20(8):980–93. http://dx.doi.
95. Weinberg GL. Treatment of local anesthetic systemic toxicity (LAST).
Reg Anesth Pain Med. 2010;35(2):188–93.
96. Masic D, Liang E, Long C, Sterk ES, Barbas B, Rech MA. Intravenous
lidocaine for acute pain: A systematic review. Pharmacotherapy.
97. Pertwee RG, Howlett AC, Abood ME, Alexander SPH, Di Marzo V, Elphick
MR, et al. International union of basic and clinical pharmacology. LXXIX.
Cannabinoid receptors and their ligands: Beyond CB1 and CB2. Pharmacol
Rev. 2010;62(4):588–631.
98. Stockings E, Campbell G, Hall WD, Nielsen S, Zagic D, Rahman R, et
al. Cannabis and cannabinoids for the treatment of people with chronic
noncancer pain conditions: A systematic review and meta-analysis of
controlled and observational studies. Pain. 2018;159(10):1932–54. http://
99. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based
medicines for chronic neuropathic pain in adults. Cochrane Database Syst
Rev. 2018;3(3):CD012182.
100. Phillips TJC, Cherry CL, Cox S, Marshall SJ, Rice AS. Pharmacological
treatment of painful HIV-associated sensory neuropathy: A systematic
review and meta-analysis of randomised controlled trials. PLoS One.
101. Fitzcharles MA, Baerwald C, Ablin J, Häuser W. Efficacy, tolerability and
safety of cannabinoids in chronic pain associated with rheumatic diseases
(fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A
systematic review of randomized controlled trials. Schmerz. 2016;30(1):
102. Abdallah FW, Hussain N, Weaver T, Brull R. Analgesic efficacy of
cannabinoids for acute pain management after surgery: A systematic review
and meta-analysis. Reg Anesth Pain Med. 2020;45(7):509–10. http://dx.doi.
103. Cheung CW, Ching Wong SS, Qiu Q, Wang X. Oral oxycodone for
acute postoperative pain: A review of clinical trials. Pain Physician.
104. Rodrigues S, Shin D, Conway M, Smulski S, Trenker E, Shanthanna H,
et al. Hydromorphone versus morphine: A historical cohort study to
evaluate the quality of postoperative analgesia. Can J Anaesth. 2020. http://
105. Weisberg DF, Becker WC, Fiellin DA, Stannard C. Prescription opioid
misuse in the United States and the United Kingdom: Cautionary lessons.
Int J Drug Policy. 2014;25(6):1124–30.
106. Macintyre PE. Safety and efficacy of patient-controlled analgesia. Br J
Anaesth. 2001;87(1):36–46.
107. McNicol ED, Ferguson MC, Hudcova J. Patient controlled opioid analgesia
versus non-patient controlled opioid analgesia for postoperative pain.
Cochrane Database Syst Rev. 2015;2015(6):CD003348. http://dx.doi.
108. Lee LA, Caplan RA, Stephens LS, Posner KL, Terman GW, Voepel-Lewis T,
et al. Postoperative opioid-induced respiratory depression: A closed claims
analysis. Anesthesiology. 2015;122(3):659–65.
109. Gupta K, Nagappa M, Prasad A, Abrahamyan L, Wong J, Weingarten
TN, et al. Risk factors for opioid-induced respiratory depression in
surgical patients: A systematic review and meta-analyses. BMJ Open.
110. Brummett CM, Waljee JF, Goesling J, Moser S, Lin P, Englesbe MJ, et al.
New persistent opioid use after minor and major surgical procedures in
US adults. JAMA Surg. 2017;152(6):e170504.
111. Chen EY, Marcantonio A, Tornetta P. Correlation between 24-hour
predischarge opioid use and amount of opioids prescribed at hospital
discharge. JAMA Surg. 2018;153(2):e174859.
112. Howard R, Fry B, Gunaseelan V, Lee J, Waljee J, Brummett C, et al.
Association of opioid prescribing with opioid consumption after surgery
in Michigan. JAMA Surg. 2019;154(1):e184234.
113. Neal JM. Ultrasound-guided regional anesthesia and patient safety: An
evidence-based analysis. Reg Anesth Pain Med. 2010;35(2 Suppl):S59–67.
114. Richman JM, Liu SS, Courpas G, Wong R, Rowlingson AJ, McGready J, et
al. Does continuous peripheral nerve block provide superior pain control to
opioids? A meta-analysis. Anesth Analg. 2006;102(1):248–57. http://dx.doi.
115. Liu SS, Strodtbeck WM, Richman JM, Wu CL. A comparison of regional
versus general anesthesia for ambulatory anesthesia: A meta-analysis of
randomized controlled trials. Anesth Analg. 2005;101(6):1634–42. http://
116. Fredrickson MJ, Krishnan S, Chen CY. Postoperative analgesia for shoulder
surgery: A critical appraisal and review of current techniques. Anaesthesia.
117. Chin KJ, Adhikary S, Sarwani N, Forero M. The analgesic efficacy of pre-
operative bilateral erector spinae plane (ESP) blocks in patients having
ventral hernia repair. Anaesthesia. 2017;72(4):452–60. http://dx.doi.
Canadian Journal of General Internal Medicine
16 Volume 16, Special Issue 1, 2021
Perioperative Medicine Special Issue
CJGIM_1_2021_176993.indd 16CJGIM_1_2021_176993.indd 16 3/22/21 6:28 PM3/22/21 6:28 PM
118. Almasi R, Rezman B, Kriszta Z, Patczai B, Wiegand N, Bogar L. Onset
times and duration of analgesic effect of various concentrations of local
anesthetic solutions in standardized volume used for brachial plexus blocks.
Heliyon. 2020;6(9):e04718.
119. Grant SA, Nielsen KC, Greengrass RA, Steele SM, Klein SM. Continuous
peripheral nerve block for ambulatory surgery. Reg Anesth Pain Med.
120. Terkawi AS, Mavridis D, Sessler DI, Nunemaker MS, Doais KS, Terkawi
RS, et al. Pain management modalities after total knee arthroplasty: A
network meta-analysis of 170 randomized controlled trials. Anesthesiology.
121. Garlich JM, Pujari A, Debbi EM, Yalamanchili DR, Moak ZB, Stephenson
SK, et al. Time to block: Early regional anesthesia improves pain control in
geriatric hip fractures. J Bone Joint Surg Am. 2020;102(10):866–72. http://
122. Narouze S, Benzon HT, Provenzano D, Buvanendran A, De Andres J,
Deer T, et al. Interventional spine and pain procedures in patients on
antiplatelet and anticoagulant medications (second edition): Guidelines
from the American Society of Regional Anesthesia and Pain Medicine, the
European Society of Regional Anaesthesia and Pain Therapy, the American
Academy of Pain Medicine, the International Neuromodulation Society,
the North American Neuromodulation Society, and the World Institute of
Pain. Reg Anesth Pain Med. 2018;43(3):225–62.
123. Bruce J, Thornton AJ, Scott NW, Marfizo S, Powell R, Johnston M, et al.
Chronic preoperative pain and psychological robustness predict acute
postoperative pain outcomes after surgery for breast cancer. Br J Cancer.
124. Waljee JF, Cron DC, Steiger RM, Zhong L, Englesbe MJ, Brummett
CM. Effect of preoperative opioid exposure on healthcare utilization
and expenditures following elective abdominal surgery. Ann Surg.
125. Huang A, Katz J, Clarke H. Ensuring safe prescribing of controlled
substances for pain following surgery by developing a transitional pain
service. Pain Manag. 2015;5(2):97–105.
126. Kaye AD, Helander EM, Vadivelu N, Lumermann L, Suchy T, Rose M, et
al. Consensus statement for clinical pathway development for perioperative
pain management and care transitions. Pain Ther. 2017:6(2):129–41. http://
127. Rapp SE, Ready LB, Nessly ML. Acute pain management in patients with
prior opioid consumption: A case controlled retrospective review. Pain.
128. Goel A, Azargive S, Weissman JS, Shanthanna H, Hanlon JG, Samman B,
et al. Perioperative Pain and Addiction Interdisciplinary Network (PAIN)
clinical practice advisory for perioperative management of buprenorphine:
Results of a modified Delphi process. Br J Anaesth. 2019;123(2):e333–42.
129. Boenigk K, Echevarria GC, Nisimov E, von Bergen Granell AE, Cuff
GE, Wan J, et al. Low-dose ketamine infusion reduces postoperative
hydromorphone requirements in opioid-tolerant patients following spinal
fusion: A randomised controlled trial. Eur J Anaesthesiol. 2019;36(1):8–15.
130. Huxtable CA, Roberts LJ, Somogyi AA, Maclntyre PE. Acute pain
management in opioid-tolerant patients: A growing challenge.
Anaesth Intensive Care. 2011;39(5):804–23. http://dx.doi.
Canadian Journal of General Internal Medicine
Volume 16, Special Issue 1, 2021 17
Mazda et al.
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