1. Trevor D. Schack, MD University of Michigan
What’s New In Acute Pain Management: Reducing Our Dependence On Opioids
Trevor D. Schack, MD
University of Michigan

2. Objectives
To review recent developments in the understanding of acute pain with focus on molecular pathophysiology and the repercussions of poorly controlled pain
To understand the role of opioids in acute pain management including new insights into their potential negative consequences
To understand current opioid-sparing strategies including multimodal analgesia and regional techniques
This morning I plan on reviewing some developments in acute pain management with a focus on opioid-sparing strategies.
Much has changed in our thinking of perioperative pain control over the last few decades. We’ll review some of the major developments with a focus on some of the underlying mechanisms responsible…
And also take a look at some new insights into potential negative consequences of opioid use such as opioid induced hyperalgesia and links to cancer recurrence.
Finally, we’ll go over opioid-sparing strategies such as regional and multimodal analgesia.

3. Introduction
Preoperatively, pain control remains one of the top concerns of patients. Headlines such as this one routinely garner much attention…
The subject of this particular article is an orthopedic surgeon…
which didn’ t surprise me too much because a few of our orthopedic surgeons at UofM frequently make the claim that their operations aren’t painful.
Joking aside, pain control remains an important issue and even most surgeons are concerned with it.
It reflects on overall patient well-being and has close ties to outcome.

4. Background 1996 – WHO Pain Ladder 1996 – APS “fifth vital sign”
2000 – JCAHO Pain Management Standards
So,
Since the 1990s there has been increased scrutiny placed on the under-treatment of pain.
The much familiar WHO pain ladder debuted in It was originally intended for cancer patients, but later adapted to a variety of medical and surgical patients. It advocates the use of opioids for moderate-to-severe pain, and non-opioid medications for mild pain.
Around the same time WHO pain ladder came on the scene, the American Pain Society introduced concept of pain as the “fifth vital sign.” Nurses and physicians everywhere to encouraged to frequently assess patients’ pain recording it as you would other physiologic parameters.
In the year 2000, The Joint Commission then JCAHO released guidelines substantiating this notion of the “fifth vital sign” placing emphasis on routine assessment of pain

5. Background
2000s – CMS introduces Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey
2/18 questions directly relating to pain
4/18 indirectly relating to pain
2010 – The Patient Protection and Affordable Care Act includes HCAHPS to calculate value-based incentive payments
This concept--routine assessment of pain--has continued to gain acceptance, and often serves as an indicator of healthcare quality.
In the 2000s CMS—the Center for Medicare and Medicaid Services--introduced the Hospital Consumer Assessment of Healthcare Providers and Systems, also called (HCAHPS), survey.
2/18 questions in this survey directly relate to pain control
and 4/18 indirectly relate to pain control
The HCAHPS survey and pain control in general remain a major focus of the current healthcare reform and pay for performance efforts.

6. Pain Control Remains Inadequate
Despite the Joint Commission standards and guidelines regarding pain control, data has indicated that many patients continue to experience intense pain after surgery.
This chart depicts the results of patient surveys before and after implementation of the JAHCO guidelines.
As you can see, there is very little difference in how surgical patients rate their pain after their operation. If anything, the “after survey,” conducted in 2003 shows a slightly greater incidence of ‘extreme’ pain.
The 2003 survey questioned 250 adult surgical patients. 80% of those reported acute pain postoperatively, and 86% had moderate-to-severe pain. These results indicate some room for improvement.
Warfield CA, Kahn CG. Anesthesiology. 1995;83:
Apfelbaum JL, et al. Anesth Analg. 2003;97:

7. Effects of Uncontrolled Pain
Patient satisfaction isn’t the only thing to be concerned about when discussing uncontrolled pain…It can also affect morbidity and mortality.
This diagram looks somewhat convoluted, but I kind of like it for that reason. Hopefully everyone can make out the small print.
Pain can have complex multisystem effects that often influence each other in ways that aren’t always readily apparent. By central, sympathoadrenal, and neuroendocrine alterations it can lead to things such as…
increased risk of infection
poor wound healing
pneumonia
deep vein thrombosis
and coronary ischemia
These complications are not only bad for the patient, but they can also cause prolonged hospitalization and drive up healthcare cost.

8. Opioid Use Increases Frasco et al (2005)
The lack of improvement seen in those surveys did not occur without trying…
Following the Joint Commission guidelines, many centers reported an increase in the overall use of opioids to treat acute and chronic pain. This is not too surprising given that opioids have been the primary “pain medication” for hundreds of years.
In the study shown here, Frasco and colleagues examined the impact of the Joint Commission Initiative on perioperative opioid consumption at the Mayo Clinic in Scottsdale.
Between the year 2000 and 2002, nurses were given additional training on the assessment of pain and pain medications. They were also given a copy of the new guidelines.
The authors found an increase in PACU morphine use from a mean of 6.5 mg (± 7.3 mg) to a mean of 10.6 mg (± 10.4 mg, P < )
As we all know, opioids do have some side effects…. (N=541 before and 541 after); req’d 3/10 VAS prior to discharge
Frasco et al (2005)

9. As Do Side Effects
Vila et al (2005) reported a more than two-fold increase in the incidence of opioid related adverse events involving over-sedation
11->24.5/100,000 patients (p < 0.001)
94% had a documented decrease in level of consciousness preceding the event
Around the same time of Frasco’s study … groups such as the Institute for Safe Medication Practices raised concern over reports of overaggressive pain management…
leading to increases in oversedation and fatal respiratory depression.
One study by Vila and colleagues published in 2005 reported more than a two-fold increase in opioid related over sedation.
94% of these cases had documented a decrease in level of consciousness prior to the event

10. Other Opioid Side Effects
Ileus/Constipation
Nausea/Vomiting
Sedation/Resp Depression
Cough suppression
Confusion/Delirium
Pruritus
Dry mouth
Sweats
Urinary retention
Tolerance/Dependence
We all know opioids have other undesirable effects as well…
They can cause ileus and constipation, prolonging hospital stays after abdominal surgery.
Nausea and vomiting are frequent
As is sedation (which can be good in some cases) but can also occur with respiratory depression
They also can cause delirium, pruritus, dry mouth, and urinary retention.
Prolonged use is associated with tolerance and dependence.

11. Cost of Adverse Events
In addition to potential mortality risk, opioid-related adverse events have been associated with an increase in cost and length of stay (Oderda, 2007)
These can all complicate a patient’s stay…
And, studies have indicated that opioid-related complications do have an impact on cost and length of stay.

12. So, What Has Changed?
So, what has changed over the last several years?

13. Advances in Understanding
Well, some of the greatest developments over the last decade have been in our understanding of pain processing.
We’ve gone from thinking of pain as a simple circuit to a much more complex network.
The picture on the left depicts Descarte’s understanding of pain in 1664 as a mechanical process travelling along a nerve to the brain. He got some of finer details wrong…something involving strings, brain valves, and animal spirits. But the overall concept was correct.
It took over 300 years to refine our understanding of the complex neural pathways involved in transmitting a signal from the periphery towards the brain.
Just within the last few decade are we beginning to understand the molecular mechanisms involved…
Descartes 1664
Today

14. Molecular Mechanisms
We have molecular biologists to thank for diagrams such as this one. Fortunately (for both myself and everyone here) I am not going to spend too much time with this.
What is important to know is that advances in the study of molecular mechanisms have increased our understanding of concepts such as:
central and peripheral sensitization of pain
opioid induced hyperalgesia
and even links between opioids and cancer recurrence
In the future understanding of these molecular mechanisms should allow for the development of novel therapeutics…
and help us understand why some people go on to have persistent pain after surgery.

15. Pain Pathophysiology
These advances in understanding have already led to some changes in the way we treat pain.
The concept of targeting pain pathways at multiple locations led to the development of multimodal analgesia.
At the level of the initial painful stimulus, NSAIDs prevent prostaglandin formation and inflammation.
In the dorsal horn of the spinal cord, epidural and intrathecal local anesthetics interrupt transmission of painful stimuli.
Modulation of pain in the spinal cord occurs with epidural and intrathecal opioids as well as alpha-2 agonists and ketamine.
Perception of pain in the cortex is altered by alpha-2 agonists, COX inhibitors, Tylenol, ketamine, and gabapentin.

16. Opioid Induced Hyperalgesia
Molecular studies have advanced our understanding of other concepts as well… In the case of opioid induced hyperalgesia, recent research suggests that a paradoxical response to opioids can occur such that patients who receive them actually can become more sensitive to painful stimuli. While typically thought of in the setting of chronic pain, this can also occur after intraoperative administration of high doses of potent opioids.
In fact infusions of high dose remifentanil are a well accepted means of experimentally inducing hyperalgesia. This can lead to increased postoperative pain despite increased opioid use. It occurs as a distinct mechanism from opioid tolerance, which can also increase postoperative opioid use.
One study by Koppert and colleagues used transdermal electrical stimulation to induce pain. Subjects were randomized to receive remifentanil infusions or saline.
You can see in graph A that the group who received the higher dose remifentanil infusion had 50% more postinfusion pain than the saline control group.
In graph B the higher dose remifentanil group also had a larger surface area of hyperalgesia.
The precise molecular mechanism of opioid induced hyperalgesia is still being worked out but is thought to involve activation of NMDA receptors as NMDA antagonists like ketamine have been shown to attenuate the effect.
*Koppert (2007)

17. Anesthesia, Analgesia, and Cancer
Lately, there has also been increased interest in the role anesthetics and analgesics have in cancer recurrence and metastases. This is a subject I’m going to spend some extra time on…
As anesthesiologists we’re often asked to manage cancer patients either for surgical resection or pain management.
Cancer remains a leading cause of morbidity and mortality worldwide. In the US it is the second leading cause of death next to heart disease.
The most common cancers contributing to mortality are lung, breast, prostate, and colorectal cancer. These vary by gender as seen in these pie charts.
We’ve become more adept at treating primary tumors, but mortality typically results from either recurrence or metastases.
*CDC 2010

18. So, why all of the interest (in cancer)?
Well, epidemiologic studies have suggested that patients who receive a general anesthetic with opioids rather than a local or regional anesthetic have greater rates of cancer recurrence.
In this retrospective study published in 2006, the authors looked at 129 patients who had undergone mastectomy for breast cancer.
50 patients had a regional anesthetic in the form of a paravertebral block in addition to a general anesthetic.
79 had a general anesthetic with opioids for pain control.
At 24 months recurrence- and metastasis-free survival was 94% (95% confidence interval, 87–100%) in paravertebral patients vs 82% (74–91%) in the general anesthetic patients.
This gap widened over a longer period--at 36 months it was 94% in the paravertebral patients vs 77% (68–87%) in the general anesthesia patients, (P = 0.012).

19. Epidural Patients 57% Lower Risk Recurrence
93%
84%
78%
49%
In another retrospective study, published in 2008, the authors looked at patients with invasive prostate cancer who underwent radical prostatectomy
with either general anesthesia and epidural analgesia
or with general anesthesia and opioid analgesia
At 3 years, 93% of the epidural patients remained disease free vs 78% of the opioid patients.
Again, the gap widened over time, and at 7 years 84% of the epidural patients remained disease free vs only 49% of the opioid patients.
After adjusting for tumor size, Gleason score, preoperative prostate-specific antigen, margins, and date of surgery….
patients who had an epidural had an estimated 57% (95% confidence interval, 17–78%) lower risk of recurrence compared to those who had opioid analgesia.
Similar data also exists for other cancer types including colorectal cancer and melanoma.
These retrospective studies do have limitations—they are subject to confounding factors…
But this data is pretty remarkable. Prospective studies are needed, but it is important to consider what mechanisms may be involved here. 3 7
Epidural Patients 57% Lower Risk Recurrence

20. Pathogenesis of Tumor Metastases
To do that it is necessary to review how metastases develop. We are going to delve here into some basic science so stay with me for a bit.
Tumor cells initially undergo a period of transformation followed by a period of growth. Nutrient supply is met by diffusion.
Later, angiogenic factors are produced and neovascularization allows for continued tumor growth.
Tumor cells then detach and invade surrounding tissue. From here they enter lymphatics or vasculature accessing the systemic circulation.
Most circulating tumor cells are destroyed by the host immune system, but those that evade it become trapped in capillary beds in the organs such as the lungs or liver.
Here they adhere to endothelial cells, extravasate, and establish new independent blood supplies.

21. Immune Response to Tumor Cells
Natural Killer Cells
Spontaneously recognize and lyse tumor cells
Activated by IL-2 and IFN-y
Patients with low levels of NK cells have increased risk for recurrence
Stress-induced attenuation NK activity in rat model is associated with breast tumor growth and metastasis
Cytotoxic T-cells
Dendritic Cells
Evasion of the host’s immune defenses are essential for the tumor cells to disseminate and metastasize. Cell-mediated immunity is the primary defense against tumor cells. The chief components of are natural killer cells, cytotoxic T cells, mononuclear cells and dendritic cells.
Of these, natural killer cells are the most important.
They are capable of spontaneously recognizing and lysing tumor cells.
They are activated by IL-2 and IFN-y. These cytokines are important regulators of the immune response.
Multiple studies show an inverse relationship between natural killer cell activity at the time of surgery and development of metastatic disease.
Furthermore, rat models show that stress-induced reduction of natural killer cell activity can enhance tumor development…
while rats who receive ‘immunstimulation’ therapy (CpG-C, propranolol and etodolac) perioperatively show survival benefit.
The other cell type worth mentioning are cytotoxic T Cells. These are a form of cellular adaptive immunity. They become sensitized to tumor cells after presentation of antigens by dendritic cells. Tumor infiltration by cytotoxic T-cells has been associated with positive prognosis in colorectal cancer.
*Dranoff (2004)

22. Surgery—A Critical Time
Surgery is the mainstay treatment for primary tumors
Can offer best prognosis for patients with solid tumors
Likely a critical period when metastases are either established or eradicated
Can result in minimal residual disease—microscopic deposits at margins or micrometastases
Fate of these neoplastic cells likely dependent on the competence of the host immune response perioperatively
Studies show the presence of neoplastic cells in circulation 24 hr following tumor resection assoc with increased recurrence
What the epidemiologic studies seem to suggest is that the perioperative period is a crucial time when metastases are either established or eradicated.
Surgical resection is the mainstay treatment for solid, primary tumors.
Ideally it results in complete excision of the tumor, but oftentimes there is minimal residual disease left behind—either microscopic deposits at the margins or micrometastases.
The fate of this residual disease is dependent upon the host immune response…
and the perioperative period is a critical time.
Studies have shown that the presence of neoplastic cells in circulation 24 hr after tumor resection is independently associated with increased cancer recurrence.

23. Effect of Surgery on Immune Function and Metastasis
Perioperative immunosuppression as a result of the neuroendocrine stress response and cytokine inflammatory response
Disrupting endothelial barriers during surgery releases tumor cells into circulation—supported by PCR
Release of growth factors—PGE2, VEGF, TGF-b
And pro-inflammatory cytokines—IL-1, TNF-a, PGE2
Decreased levels of anti-angiogenic compounds—endostatin, angiostatin
Surgery has been shown to accelerate the development of existing metastases and promote new ones. (Ben-Eliyahu)
This is thought to occur primarily from suppression of cell-mediated immunity. While the underlying mechanisms have not been completely established, neuroendocrine stress and cytokine inflammatory responses are thought to play a role.
This immune-suppression occurs within hours, can last for days, and is proportional to the extent of surgical trauma.
For example there is a more profound immunosuppression associated with decreased natural killer cell activity in patients that undergo thoracotomy vs a thorascopic VATS procedure.
Surgery also invariably causes disruption of tumor cells and endothelial barriers. This releases tumor cells into systemic circulation.
In fact, tumor cells can be detected in a patients blood by PCR and levels are known to increase during surgery.
Furthermore, surgery can induce the release of growth factors that promote angiogenesis such as vascular endothelial growth factor and prostalanding E2.
Prostaglandin E2 also inhibits the function of NK cells, CTCs, and dendritic cells.
Surgery can also cause a reduction of factors that oppose angiogenesis such as endostatin and angiostatin.
Taken together these effects can be fairly significant.

24. Effect of Pain on Immune Function and Metastasis
Pain is a potent stimulant of the HPA axis and sympathetic nervous system, which can lead to immunosuppression
Acute pain suppresses NK cell activity and promotes tumor development in animals
Analgesia has been shown to attenuate this effect
Pain itself is known to be a cause of immunosuppression post-operatively. It is a potent activator of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. This activation of stress response can suppress cellular immunity.
In fact, acute pain has been shown decrease natural killer cell activity and promote tumor development in animal models.
Not surprisingly, analgesia has been shown to attenuate the effect.
This chart depicts natural killer cell activity in rats.
The first group had just general anesthesia
The second, general anesthesia with administration of fentanyl
The third surgery with general anesthesia
The fourth had surgery with general anesthesia and fentanyl.
Blood samples were drawn 5 hours after surgery or general anesthesia.
The group that had surgery without any analgesics showed suppressed natural killer cell activity postoperatively.
Additionally, they displayed a 4-four higher retention of tumor cells in the lungs than the general anesthesia control group after being inoculated with tumor cells 5 hours after surgery.
The groups that received analgesia fared better.
4x Tumor Retention
*Page (2001)

25. Levels IL-1 and IL-6 With Different Analgesics
But not all analgesics appear to be equal. We have seen in epidemiologic studies that regional analgesia is associated with lower cancer recurrence rate than with opioids. The exact mechanism by which this occurs is unknown, but it is thought to include inhibition of the neuroendocrine stress response and immunosuppressive effects of surgery.
One study supporting this concept looked at 115 patients undergoing elective lower abdominal surgery and examined the effects of intermittent opioids, opioid PCA, and epidural analgesia on several immune functions.
Figure A depicts blood levels of IL-1, one of the proinflammatory cytokines known to impair cellular immunity; 24, 28, and 72 hrs after surgery.
IL-1 levels in the epidural patients remain near 0 up to 72 hours after surgery, while the patients receiving opioids have elevated levels.
Figure B shows similar results for for IL-6, another proinflammatory cytokine.
These results seem to indicate that regional anesthesia lowers the stress response to surgery. We also know that regional techniques have the ability to reduce postoperative opioid requirements… And it has been known for some time that opioids themselves have immunosuppressive effects….
*Beilin (2003)

26. Opioids and Immune Function
NK Cell Activity In Rats With Various Opioids
NK Cell Activity In Humans
*Beilin 1989
*Beilin 1996
Both perioperative and chronic opioid use have been shown to suppress cell-mediated and humoral immunity… This includes NK cell activity, production of immune-stimulating cytokines, phagocytic activity, and antibody production.
The first figure depicts natural killer cell activity in rats after administration of fentanyl, sufentanil, and morphine.
Animals received an injection of saline or naltrexone followed 20 min later by an injection of saline or opioid.
The opioid groups show suppression of NK cell activity that is reversed by the opioid antagonist, naltrexone.
This suppression also occurs in humans. The second figure depicts natural killer cell activity in low-dose (6 mcg/kg) and high-dose fentanyl (75 mcg/kg) groups.
At 24 hours after surgery both groups had similar suppression of NK cell activity….
But, this was more prolonged in the high dose group lasting beyond the second postoperative day.
In another study not depicted here, healthy volunteers showed suppression of several components of cell-mediated immunity including NK cells after a morphine infusion (*Yeager 1995). It is clear that opioids have an immunosuppressive effect, but keep in mind that pain itself can also be immunosuppressive. This makes it incredibly difficult to study whether opioid-induced immunosuppression can lead to tumor progression in vivo, and there is a lack of evidence in this area.
Both cellular and humoral immunity are suppressed by perioperative and chronic opioid use
NK cell activity is reduced by opioids
Whether this indirectly promotes cancer recurrence and metastasis is unknown

27. Opioids—Direct Effect on Cancer Progression?
Breast Tumor Volume In Mice
control (▪)
morphine (▵)
morphine + naloxone (□)
naloxone (▴)
*Gupta (2002)
Beyond any indirect immunosuppressive effects, opioids may actually exert direct influence tumor progression. One mechanism by which this may occur is through stimulation of angiogenesis.
Gupta and colleagues were able to show that morphine in clinical concentrations has the ability to stimulate human endothelial cell proliferation and angiogenesis.
Breast cancer cells implanted in mice had significantly increased tumor volume and vascularization when treated with morphine.
In figure A this is represented by the white triangles.
This effect was blunted by the opioid antagonist naloxone which are depicted by the white squares. (The treated with vehicle (▪), morphine (▵), morphine plus naloxone (□), or naloxone (▴) .)
Further molecular studies have suggested that these effects may be due to direct stimulation of the mu opioid receptor itself or its interaction with the vascular endothelial growth factor receptor. One proposed mechanism is shown in the second figure.
*Lennon (2012)
Breast cancer cells implanted in mice show increased tumor volume and vascularization when treated with opioid
Likely through direct stimulation Mu receptor or its interaction with VEGF receptor

28. Role For μ-Opioid Receptor?
NSCLC cells show 5x increase in MOR expression
Silencing MOR in animal model causes reduced tumor growth (35-50%) and metastasis (45-70%)
Similar results are obtained with a naltrexone infusion
Lung cancer cells injected into MOR knockout mice show no tumor development
Same cells injected into controls developed lethal tumors in 12 days
Looking into this further a group out of the University of Chicago carried out a series of cellular, tissue, and in vivo studies assessing the role of the MOR in cancer progression. By analyzing human lung tissue and nonsmall cell lung cancer lines using an immunohistochemical assay, they found that MOR expression was increased in cancer cells more than 5-fold.
They were able to silence the mu-opioid receptor in lung cancer cells implanted into the mice using plasmids encoding for short hairpin RNA
Doing this they found both reduced tumor growth (35-50%) and metastasis (45-70%).
Opioid antagonism with methylnatrexone showed similar reductions in tumor growth and metastasis.
Most dramatically… they found that when Lewis lung carcinoma cells were injected into MOR knockout mice, no tumors developed. Zero tumors.
The same cells injected into control mice developed lethal tumors within 12 days. This is illustrated in the figure.
The authors suggested that one explanation for this finding may be that the MOR is required for tumor angiogenesis.
Taken together, these results strongly suggest a direct role for the MOR in cancer growth and metastasis.
*Mathew (2011)

29. Most common polymorphism in MOR Results in decreased responsiveness
MOR With A118G Polymorphism
Survival Probability in Carriers of A118G
Most common polymorphism in MOR
Results in decreased responsiveness
5% African-American women
24% Caucausian
The knowledge of this potential link has led to some more recent clinical studies. In the study depicted here, Borstov and colleagues looked into whether a common genetic MOR polymorphism affected outcomes for patients with breast cancer.
The A118G polymorphism is the most common MOR polymorphism. It is depicted in the first figure as one of the red dots within the plasma membrane.
Functionally, this polymorphism results in decreased responsiveness of the MOR.
Knowing this, it was hypothesized that breast cancer patients who had this particular polymorphism would have increased survival.
Over 2000 women were studied. 5% of African-American women and 24% of Caucasian women carried one or two copies of the gene in question.
In the second figure, women with one copy of the allele are the A/G group and women with two copies are the G/G group.
Of the women without the polymorphism--A/A geno-type--and invasive cancer, 17% (291 of 1,682) died of the disease versus only 8% (27 of 345) of the women with the G allele (P ).
A similar study published this past year found that patients with the homozygous G/G genotype had a lower risk of developing esophageal cancer. (Wang 2013)
*Borstov (2012)

30. For every 5 mg/d MEQ, risk of progression incr 8% and death 5%
MOR expression and long-term requirement independently associated with inferior survival
For every unit MOR + area, risk of cancer progression incr 65% and death 55%
For every 5 mg/d MEQ, risk of progression incr 8% and death 5%
This last study I’ll show you with regard to cancer was just published in December. It is another retrospective analysis looking at 113 patients with stage IV prostate cancer. This study differed from the others in that not only did it look at MOR expression but also long-term opioid use.
They found that both MOR expression and long term opioid requirement were independently associated with inferior progression-free survival as well as inferior overall survival.
For every unit increase in MOR positive area in prostate tissue the risk of progression increased by 65% and the risk of death increased by 55%.
For every 5 mg/day increase of morphine equivalents, the risk of progression increased 8% and death 5%.
Furthermore, the MOR was found in the cell membrane of samples with high expression whereas it was found in the cell nucleus in samples with low expression.
This is consistent with prior studies of colon and lung cancer.
One explanation for this is that membrane-associated MOR is active and stimulates downstream signaling
Whereas the nuclear MOR is an internalized, inactive receptor.
Again, this evidence suggests a strong role for the MOR in terms of cancer growth and recurrence. That said, these studies are retrospective and subject to a variety of confounding factors.
*Zylla (2013)
15% survival in high MOR group vs 70% in low MOR

31. Future Prospective Studies
*Heaney (2012)
Several prospective clinical studies are underway exploring the effect of opioid-sparing techniques on cancer recurrence.
The majority are comparing some form of regional analgesia to opioid analgesia in cancer patients with primary outcomes of disease-free survival or cancer recurrence.
A few are listed above. Most won’t be completed for several years.
Until these are complete it may be inadvisable to change current practice. Remember that poor analgesia has also been associated with cancer recurrence.

32. “Whenever possible, anesthesiologists should use multimodal pain management therapy. Central regional blockade with local anesthetics should be considered.”
Although complete abandonment of opioids is inadvisable, it is important to note that current ASA guidelines for Acute Pain Management favor the use of regional and multimodal pain strategies “whenever possible.”
It is likely reasonable to incorporate some of these opioid-sparing techniques into practice as long as analgesia isn’t compromised.
I’ll review some of these options now starting with a few regional techniques.

33. Regional Anesthesia/Analgesia
Increased patient satisfaction
Improved analgesia
Decreased postoperative opioid use
Regional anesthesia is generally associated with increased patient satisfaction, improved analgesia, and decreased postoperative opioid use.
A full review of the topic is outside the scope of the talk.
I am going to skip upper and lower extremity blocks altogether, but I would like to bring up a couple of blocks that have seen increased popularity.

34. Transversus Abdominal Plane (TAP) Blocks
First described by Rafi et al (2001)
Provides analgesia to the abdominal wall
Blocks anterior divisions of lower thoracic, subcostal and first lumbar nerves between IO and TA muscles
Efficacy established by RCT
Dye studies show reliable spread T10-L1 (iliac crest to costal margin)
External oblique
Internal oblique
Transversus abdominis
The first is a transversus abdominal plane block or TAP block. It is a relatively newer regional technique used to provide somatic analgesia after abdominal surgery.
It involves depositing local anaesthetic into the anatomic plane between the internal oblique and transversus abdominis muscles. Originally described by Rafi in 2001, it was referred to as an abdominal field block, and performed using an anatomic landmark technique.
The introduction of ultrasound piqued interest in the block—with ultrasound the muscle layers of the abdomen are easily visualized and the block itself is simple to perform with improved success.
Its efficacy has been established by RCT and dye studies have shown reliable spread from T10-L1.
Quadratus lumborum

35. TAP Blocks For Donor Nephrectomy at UM
Donor Nephrectomy Incisions
At U of M we began using TAP blocks as part of an “Enhanced Recovery Program” for donor nephrectomy patients.
When performed laparoscopically, donor nephrectomies involve smaller incisions, less pain, and quicker recoveries. They do however require at least one larger incision to remove the donor kidney. This is commonly made as a low transverse “Pfannenstiel” type incision and often accounts for the majority of a patient’s pain complaints postoperatively.
The charts show some preliminary unpublished data. You can see that while postoperative pain scores only decrease by 1 point, narcotic requirements are cut in half.
Average Daily Narcotic Pre-TAP Block – MEQ versus Average Daily Narcotic with TAP MEQ (Total Narcotics Pre-Tap Block – mg versus Total Narcotic with TAP – 24.31, N=15).
This is consistent with prior published data which have shown 50-70% opioid reduction for a variety of procedures.
With theses results the block has gained traction and we’ve had requests from other surgeons to perform it for a variety of operations.

36. TAP Indications
Best for lower abdominal and pelvic incisions from the umbilicus and below
Donor nephrectomy
‘Hand-assist’ lap port
Appendectomy
Hysterectomy
Cesarean Section
Alternative when epidural is not possible or ‘overkill’
Smaller incision/outpatient surgery
Unable to tolerate placement
Coagulopathy
Infection
Spinal abnormalities

37. TAP Technique
As mentioned before, ultrasound has drastically simplified this block and has made it quite easy to master. There are a few different approaches but this lateral one is the most commonly used.
One nice characteristic about this block is that it does not require an awake patient and can be performed under GA. It may even be safer this way because you don’t risk sudden movements which may inadvertently lead to intraperitoneal needle placement. We typically start scanning the patients with the ultrasound immediately after the induction agents are given.
A linear probe can be used for fitter patients, but at Michigan we more often than not require a curvilinear probe to reach adequate depth. The probe is placed along the midaxillary line between the subcostal margin and the iliac crest. In this location the muscle layers should be easy to identify. Oftentimes peristalsis from the bowel can be seen below the transversus abdominis in the peritoneal cavity.
A standard block needle is advanced in plane from an anterior to posterior direction until it is positioned between the IO and the TA. At this point a small volume of NS is injected to verify that the needle is in the correct plane. It should appear as a convex shape splitting the plane. Then ml of local anesthetic are injected. For midline incisions or those that cross midline, the block must be performed on both sides for adequate analgesia.

38. Paravertebral Blocks
First described in 1905 by Sellheim, a German physician
Fell out of practice until 1979
Efficacy supported by multiple RCTs
Complications are reportedly low with most feared being pleural puncture and pneumothorax (0.5%)
Cochrane Review 2013: may prevent persistent postsurgical pain after breast surgery in 1 out of every 4-5 patients
Another technique that has seen a resurgence are paravertebral blocks, particularly in the thoracic region. These can be performed either as single injections or with continuous catheters. This is the regional anesthetic that was associated with a decreased recurrence of breast cancer after surgery in one of the retrospective studies I mentioned earlier.
Unlike TAP blocks it was actually developed quite a long time ago in 1905 by a German physician. It disappeared from practice until 1979 when it was reintroduced by Eason and Watson. Since that time it has gained in popularity and ultrasound techniques have been developed.
Multiple RCT have shown better postoperative pain control with few adverse effects, particularly for breast surgery. Patients have reduced incidence of nausea and vomiting and shorter length of stay.
The most feared complications are pleural puncture and pneumothorax but these occur in less than 1% of patients, and the use of ultrasound has helped mitigate some of the risk.
A meta-analysis of small, nonblinded trials demonstrated that paravertebral blocks can provide comparable pain relief to thoracic epidurals for thoracic surgery and are associated with less nausea and vomiting, urinary retention, failed blocks, hypotension, and pulmonary complications
Perhaps most significant, a Cochrane review published in April of 2013 found that paravertebral blocks likely prevent persistent postsurgical pain after thoracotomy or breast cancer surgery. And amazingly, this may occur in one out of every four to five patients treated. (Andreae 2013)

39. Paravertebral Indications
Best for thoracic procedures but can be performed from cervical to lumbar region
Good alternative to epidural
Single-shot
Breast surgery (T2-T6)
VATS (varies)
Small umbilical hernia (T7-T10)
Prostatectomy/hysterectomy (T10-L1)
Continuous
Breast surgery (T2-3)
Lateral nephrectomy (T6-7)
Thoracotomy/VATS (T4-5)
Rib fractures (varies)
Major abdominal (T7-8)
Pelvic (T10-11)
Single shot paravertebral blocks are most commonly used for thoracic procedures, particularly breast surgery with or without axillary lymph node dissection.
But they can also be used for inguinal and umbilical hernia repair, VATS procedures, and prostatectomy or hysterectomy.
For more extensive surgery and those requiring longer hospital stays, a continuous technique is preferred where a catheter is threaded, similar to an epidural.
These can also be used for rib fractures at the level of injury. In this situation they may be preferred to epidurals as they can be used safely and effectively in patients receiving Lovenox for thromboprophylaxis.

40. Paravertebral Anatomy
Reviewing the anatomy in cross-section, the thoracic paravertebral space appears triangular shaped. It is marked in red here.
The medial border is the spinal column including the vertebral bodies, posterior elements, and the intervertebral foramen with which it may communicate with
The anteriolateral border is formed by the parietal pleura
and the posterior border is formed by the superior costotransverse ligament– this ligament extends from the inferior aspect of the transverse process above to the superior aspect of the rib tubercle below
The apex of the triangle communicates with the intercostal space laterally
There is no known cephalad limit and the caudally it likely extends to the psoas ms at L1. Therefore solution injected can spread up and down levels
As depicted above, the thoracic prevertebral space is transversed by the intercostal or spinal nerves, intercostal vessels, dorsal rami, rami communicantes, and the sympathetic chain
*usra.ca

41. Classic Technique Identifty spinous processes
Entry point 2.5 cm lateral
Contact transverse process
Redirect caudally to “walk-off”
Advance 1 cm
Inject 5 ml local anesthetic
Repeat for additional levels
Classically, the procedure is done via landmarks.
With the patient in a sitting position the spinous processes of the desired levels are identified
Then an entry point is selected 2.5 cm lateral to this
The skin and subcutaneous tissue are injected with local anesthetic then a quincke or block needle is used to contact the transverse process of the selected level. This usually occurs at a depth of around 3-4 cm in the mid-thoracic region
The depth is noted and the needle withdrawn then redirected caudally to walk under the transverse process
The needle is then advanced 1 cm beyond the transverse process. Occasionally some LOR is felt as it passes through the superior costotransverse ligament
At this point approximately 5 ml of local anesthetic are injected

42. Ultrasound Technique *Narouze (2010)
Several ultrasound-guided techniques have also been developed. Initially ultrasound was simply used to locate the transverse processes and relevant anatomy prior to carrying out the classical approach. This has graduated to performing the block under live ultrasound.
One in-plane ultrasound technique uses a paramedian oblique sagittal view of the thoracic paravertebral space with the ultrasound probe placed longitudinally.
Some have found that the view is improved when the ultrasound beam is positioned in a slightly oblique axis with the transducer tilted slightly laterally or outward.
*Narouze (2010)

43. Ultrasound Technique *Narouze (2010)
The needle is advanced in a caudal to cranial orientation in plane with the ultrasound beam. The trajectory is shown here.
The needle is advanced until the lower portion of the transverse process is contacted.
Then it can be advanced underneath the lower border of the transverse process.
Local anesthetic is then injected. Anterior displacement of the pleura and widening of the paravertebral space should occur.
Depending on the volume used, it can often be seen spreading to contiguous levels.
*Narouze (2010)

44. Thoracic Epidural Analgesia
Analgesia: lower pain scores than with systemic opioids
CV: reduced risk of MI and dysrhythmias
GI: earlier return of bowel function
Pulm: reduced risk of pulmonary complications, reduced mechanical ventilation
Endo: decreased postop protein catabolism and hyperglycemia
When there are no contraindications, thoracic epidural analgesia remains an attractive option for procedures involving the chest and abdomen.
Its benefits are well-established. Multiple studies have shown superior analgesia when compared to systemic opioids. Additionally, its use is associated with better outcomes, particularly in patients with moderate to severe comorbid diseases.
Postoperatively, it facilitates earlier mobilization, reduced ileus, and earlier resumption of oral nutrition. Additionally, it minimizes postoperative insulin resistance, and attenuates postop hyperglycemia and protein catabolism.
*Manion (2012)

45. Thoracic Epidural Analgesia
Excellent for larger incisions
Benefit less well established for minimally invasive procedures
Higher systemic side effect profile than TAP or paravertebral blocks
Can be associated with hypotension, N/V, urinary retention, numbness, weakness
Require personnel to manage on floor
They are particularly well-suited for operations involving moderate-to-large thoracic or upper abdominal incisions. Thoracotomy, esophagectomy, pancreatectomy, hepatic resection, AAA repair, and bowel resection are all procedures which can benefit from it.
Benefits for minimally invasive surgery and laparoscopic procedures are less well-established and often placement is not recommended for these operations.
They do have a higher side effect profile than TAP or paravertebral blocks. Hypotension, N/V, and urinary retention are not too uncommon.
Finally, other medical staff including surgeons are known to be quite creative when it comes to additional epidural side effects, so having someone around to manage them and dispel myths is a must.
*Manion (2012)

46. Opioid-Sparing Medications
Gabapentinoids
NSAIDS/COX Inhibitors
Acetaminophen
Local Anesthetics

47. Gabapentinoids General: Mechanism: Pharmocodynamics:
Decrease pain scores and opioid use
Likely effective at reducing chronic postsurgical pain
Side effects include sedation, dizziness, visual disturbances
Mechanism:
Structural analogs of GABA but do not bind to its receptor
Bind to voltage-gated calcium channels, modulating the release of excitatory neurotransmitters
Pharmocodynamics:
Gabapentin absorption is limited to a small portion of the duodenum while pregabalin is absorbed throughout the small intestine
Gabapentin absorption can be significantly impaired by antacids
Both are renally excreted without significant metabolism
Gabapentenoids are some of the most useful opioid-sparing medications in the perioperative period. They are effective, well-tolerated, and have few drug interactions or precautions making them useful in almost every patient. Even massive overdose can be managed with only supportive care.
Both gabapentin and its cousin pregabalin or lyrica are indicated for post herpetic neuralgia and seizure disorders
Lyrica holds additional FDA approval for fibromyalgia and diabetic neuropathy/spinal cord injury
However, multiple studies support their use in the perioperative period with reduction in pain scores and opioid use
There is even data to support a reduction in the development of chronic postsurgical pain
Side effects generally mild including sedation, dizziness, headache, and visual disturbances but can be relieved with dose adjustments
There is even some data that suggests that gabapentin reduces postoperative delirium and pregabalin may reduce vomiting. This is probably due to a reduction in opioid use.
Mechanistically, they are structural analogs of gamma-aminobutyric acid, but do not act at the GABA receptor
Instead they bind voltage gated calcium channels and modulate the release of excitatory neurotransmitters such as glutamate
There is also some evidence that they stimulate noradrenergic pain-inhibiting pathways in the brain and spinal cord
One of the principal differences between the two drugs relates to bioavailability.
Gabapentin is absorbed only in a small portion of the duodenum, while Lyrica is absorbed throughout the small intestine
This is important because once gabapentin absorption is saturated, progressively higher doses of gabapentin do not equate to higher blood concentrations
Lyrica on the other hand demonstrates linear uptake and may have both increased efficacy as well as side effects at higher doses
Additionally, gabapentin but not lyrica absorption is significantly impaired by antacids, even given 2 hr after dosing. This is important perioperatively if Bicitra or H2 blockers are used
Both are renally excreted and require dose adjustments for impairment ET1/2: hr (gabapentin) and hr (Lyrica)

48. Gabapentinoids—What Dose and When?
Timing of Dosing
Studies indicate that postop dosing is just as effective as preop
Peak plasma level in 1-2hr but peak CSF level in 6-8 hr
So, preop dosing may have to occur earlier for max benefit
Dose
Studies looking low ( mg) vs high ( mg) doses of gabapentin favor higher dosing
The same is true for pregabalin
Continuing medication thru recovery probably most effective
How much to give and when are the subject of much debate. Fortunately, it has been the subject of a number of studies
Human trials comparing dosing of gabapentin pre and post incision show no difference in opioid consumption or pain scores. (Other studies have shown a slight benefit in pain scores over the first 24 hrs in patients receiving a postop dose)
In fact, a Cochrane review of the subject concluded that gabapentin is effective in already established acute postoperative pain
So failure to give a dose preop should not dissuade you from postoperative dosing
Another important consideration is that while peak plasma levels of the drug occur at 1-2 hours after oral administration, peak CSF levels do not occur for 6-8 hours. So, for full effect these medications may need to be given substantially earlier.
With regard to dosing, studies comparing low dose regimens ( mg of gabapentin) versus high dose regimens ( mg of gabapentin) preoperatively show significantly reduced postoperative pain scores and opioid consumption for the higher dose group.
The same is true for pregabalin.
Even more importantly, continuing gabapentin or pregabalin postoperatively during recovery is probably more effective than a single dose of either medication.
A recent review published by Schmidt and colleagues in Anesthesiology recommended either 300 mg of pregabalin or 1200 mg of gabapentin preoperatively with either 150 mg twice daily of pregabalin or 600 mg tid of gabapentin on each postoperative day
*Schmidt (2013)

49. COX Inhibitors

50. COX Inhibitors among the most widely used medicines in the world
anti-inflammatory, analgesic and antipyretic activity
The anti-inflammatory and analgesic efficacies are thought to be mainly due to inhibition of the inducible COX-2.
concern regarding the cardiovascular safety of coxibs has been raised
COX-1 was described as a constitutive “housekeeping” enzyme that is expressed ubiquitously and mediates physiological responses.
It is the only isoenzyme found in platelets, leading to the formation of thromboxane A2 (TXA2).
In contrast, COX-2 is highly expressed by cells involved in inflammation (e.g., macrophages, monocytes, and synoviocytes), and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters.
COX-2 has emerged as an inducible isoform that is primarily responsible for the synthesis of prostanoids involved in acute and chronic inflammatory states.

51. COX Inhibitors Nonspecific NSAIDs (COX 1 and 2 activity)
Ketorolac, Ibuprofen
Use limited perioperatively due to platelet dysfunction, GI and renal toxicity
Coxibs (COX 2)
Celebrex
Potential cardiac/renal toxicity
Reduced GI side effects, no platelet inhibition
Both
May lead to dose-dependent increase of cardiovascular toxicity and impaired osteogenesis
15-55% reduction in perioperative opioid use (Elia 2005)

52. COX Inhibitors and Cancer
Induce apoptosis
Decrease levels of angiogenic factors
Decrease microvascular density in animal models
Attenuate opioid-induced immunosuppression
COX-2 inhibitiondecreased PGE2direct impact on cancer cell mutation, proliferation, and survival
Overexpression of COX-2 is associated with increased cancer recurrence and is a poor prognostic indicator
Farooqui et al—mouse model showed chronic morphine use increases COX-2 expression in tumor cells, and can impair analgesia while promoting tumor angiogenesis

53. Tylenol—Now Available By IV
Effective, well tolerated
Caution with severe hepatic impairment
Safe with renal dysfunction
Max 3g/day
1g IV acetaminophen reduced morphine use after orthopedic surgery approximately 30% (Sinatra, 2005)

54. Liposomal Bupivacaine
Exparel – bupivacaine loaded in multivesicular liposomes
FDA approved for local infiltration
Hemorrhoidectomy
Bunionectomy
No delay in wound healing after orthopedic surgery
Acceptable adverse effect profile
One newer drug available that may really change practice in the future is liposomal bupivacaine. We all know that bolus injections of local anesthetics are limited in duration.
The alternative, placing perineural catheters, requires extra resources—the need for a pump, patient education, and sometimes homecare. Furthermore, they can be complicated by infection, intravascular placement, or migration. This is where a longer acting local anesthetic could be useful.
Liposomal bupivacaine is bupivacaine loaded in multivesicular liposomes. These form a honeycomb-like structure that holds water soluble drugs in the core of each vesicle. The vesicles are composed of a phopholipid bilayer similar to cell membranes.
It is FDA indicated for both for local infiltration with hemorrhoidectomy and bunionectomy
In the study for use in hemorrhoidectomy it was compared to placebo. They noted that 59% of patients were opioid free at 12 hours compared to 14% in placebo group.
In the study for use in bunionectomy it was again compared to a placebo. They found markedly reduced pain scores at both 24 and 36 hours post injection but no difference from placebo at 48 hours.
You might be wondering how well this works for nerve blocks…
*Chahar (2012)

55. Attempted dose response study for 14 volunteers having femoral n block
Tested quad strength and tolerance to electrical current
Found dose response in opposite direction—higher the dose, lower the effect
This study was just published in the November issue of Anesthesia and Analgesia. Ilfeld and colleagues tried to construct a dose response study of liposomal bupivacaine for peripheral nerve blocks.
14 healthy volunteers received varying doses of liposomal bupivacaine for femoral nerve block—from 0 to 80 mg.
They tested maximum voluntary isometric contraction of the quadriceps muscle as well as tolerance to electrical stimulation in the femoral distribution at the medial knee.
The results were a bit unexpected in that they did reveal a dose response but in the opposite direction—the higher the dose the lower the observed effect.
Moreover, there was no association between dose used and time to maximum motor block, yet increases in dose did cause increased time until sensory block.
The block lasted greater than 24 hours in all subjects.
Further studies are needed to explain the mechanism behind this paradoxical effect.

56. Other Adjuvants Alpha-2 Agonists Clonidine, dexmedetomidine
Can provide sedation, hypnosis, anxiolysis, sympatholysis and analgesia
Antinociceptive effect due to action on alpha-2 receptors in brain and spinal cord
Can cause profound hypotension, bradycardia
Meta-analysis shows 20-25% reduction morphine at hrs postop (Blaudszun, 2012)
NMDA R Antagonists
Ketamine
At subanesthetic doses (0.5 mg/kg) may exert NMDA blockade modulating central sensitization and OIH
Hallucinations, bad dreams, dizziness, blurred vision
Inhibits NK cell activity in animal models

57. The Future PROSPECT (Procedure Specific Postoperative Pain Management)
PROSPECT
Procedure-specific, evidence-based recommendations
Developed by an international group of anesthesiologists and surgeons…currently chaired by a French anesthesiologist
They provide specific preop, intraop, and postop recommendations with graded levels of evidence
They even have recommendations for future areas of study

58. The Future
Enhanced Recovery Programs

59. Questions???