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NSAIDS AND OTHER PHARMACOLOGIC TREATMENT

CASE 43-2

QUESTION 1: S.L., a 67-year-old woman, presents to her primary-care physician with increased pain and

stiffness in her left knee. S.L. reports her left knee as “weak,” and she has difficulty getting out of bed in the

morning and after sitting on the recliner for some time. She has tried acetaminophen 1,000 mg 4 times daily for

1 month without adequate relief. She also takes metoprolol succinate 50 mg daily, lisinopril 20 mg daily,

ranitidine 150 mg twice daily, and citalopram 20 mg daily. Her medical history includes hypertension, osteopenia,

depression, gastroesophageal reflux disease, osteoarthritis, and a right knee replacement 2 years ago. Her

recent laboratory values and vitalsigns include the following:

BP, 160/78 mm Hg

HR, 76 beats/minute

Height, 66 inches

Weight, 190 pounds

BMI, 30.7 kg/m

2

Sodium, 145 mEq/L

Potassium, 4.8 mEq/L

BUN, 16 mg/dL

Creatinine, 1.2 mg/dL

eGFR, 48 mL/minute

WBC, 4.5 × 10

3

/μL

RBC, 4.2 × 10

6

/μL

Hemoglobin, 12.1 g/dL

Hematocrit, 36.6%

Select and recommend a medication to provide adequate pain relief for S.L.

In this patient who has failed an adequate trial of acetaminophen, therapeutic

options include celecoxib, a nonselective NSAID, tramadol, or an opioid analgesic.

There are no data to suggest any particular NSAID is more effective than another.

29

S.L. does not have any known history of coronary heart disease or peptic ulcer

disease. On the basis of the risk factors identified in Table 43-1, S.L. has one risk

factor of age, placing her at moderate risk for GI ulceration. Data suggest appropriate

treatment of Helicobacter pylori, if present, reduces the risk of GI ulceration in

patients taking NSAIDs chronically.

30 Therefore, if the decision is made to

recommend a nonselective NSAID, then ranitidine would need to be discontinued

because of a lack of protection against gastric ulcers, and a proton-pump inhibitor

(PPI) such as omeprazole should be initiated to prevent GI bleeding. Either option

would represent a reasonable therapeutic recommendation.

Table 43-1

Recommendations for NSAID Selection Based on Gastrointestinal and

Cardiovascular Risks

30

Risk Category Low GI Risk Moderate GI Risk High GI Risk

0 risk factors 1–2 risk factors Multiple risk factors, history of

previous ulcer events, or continued

use of corticosteroids or

anticoagulants

Low CV risk NSAID alone NSAID +

PPI/misoprostol

Alternative therapy or COX-2 +

PPI/misoprostol

High CV risk (low-dose

aspirin required)

Naproxen +

PPI/misoprostol

Naproxen +

PPI/misoprostol

Alternative therapy recommended

COX-2, cyclooxygenase-2 inhibitor; CV, cardiovascular; NSAID, nonsteroidal anti-inflammatory drug; PPI, protonpump inhibitor.

Table 43-2

Relative Selectivity of Cyclooxygenase Inhibitors

67

5- to 50-fold COX-2 Preferential <5-fold COX-2 Preferential COX-1 Preferential

Etodolac

Meloxicam

Celecoxib

Diclofenac

Sulindac

Meclofenamate

Piroxicam

Diflunisal

Fenoprofen

Ibuprofen

Tolmetin

Naproxen

Aspirin

Indomethacin

Ketoprofen

Flurbiprofen

Ketorolac

Based on log IC80

inhibition ratios COX-2/COX-1.

For those patients with insufficient pain relief from acetaminophen or topical

agents, an oral NSAID should be considered. As with any decision regarding

pharmacotherapy, the safety and efficacy of the chosen therapy needs to be evaluated

in the context of a patient’s specific case. The historical perspective and the

knowledge of increased cardiovascular risk versus GI safety with COX-2 agents

have had a tremendous impact on the use of these agents in clinical practice.

Currently available NSAIDs have comparatively unique characteristics in terms of

their ability to inhibit COX-1 (constitutive) and COX-2 (inducible). See Table 43-2

for selectivity of COX-2 inhibition.

Patients at increased risk for cardiovascular disease include those with unstable

angina, a history of myocardial infarction, coronary artery bypass surgery, ischemic

stroke, or a high Framingham risk score.

31 Some clinicians have recommended the

addition of low-dose aspirin 81 mg to attenuate the increased risk of cardiovascular

disease; however, this practice has not been the primary focus of vigorous clinical

trials. The addition of aspirin can potentially increase the risk of GI ulceration and

compromise cardioprotection.

32 Additionally, randomized controlled studies have not

clearly demonstrated the efficacy and safety of this approach.

31,33

In a 52-week double-blind study comparing the cardiovascular outcomes of

patients with OA exposed to ibuprofen, naproxen, or lumiracoxib, several key

findings emerged. First, ibuprofen users taking aspirin had the highest risk of

cardiovascular outcomes and heart failure in comparison with lumiracoxib. This

supports concerns that ibuprofen can competitively interfere with the ability of

aspirin to inhibit platelet aggregation.

34 Second, patients taking naproxen without

aspirin had the best safety profile with regard to cardiovascular outcomes. Whether

or not naproxen has the lowest risk for cardiovascular side effects has not been

clearly elucidated. In fact, recent analysis from the Women’s Health Initiative

suggests naproxen, in addition to NSAIDs with cyclooxygenase-2 preferential

inhibition, exhibits increased risk for cardiovascular events.

35 Conflicting data

regarding dose, duration of therapy, and methodological differences in trials have not

yet produced clear and concise evidence.

36 Lastly, heart failure was observed more

frequently in patients taking ibuprofen than in patients receiving lumiracoxib or

naproxen.

37

In a recent AHRQ report, celecoxib has been reported to increase the

risk for myocardial infarction, particularly at higher doses.

27 Other studies have

failed to exhibit this finding.

38

In summary, for patients with low cardiovascular risk

and moderate-to-higher risk for GI bleeding, a recommendation can be made for

once-daily celecoxib or NSAID plus PPI or misoprostol. However, in patients with a

higher risk for cardiovascular disease, consider the use of tramadol or naproxen, or

nonacetylated salicylates (e.g., diflunisal or salsalate) with careful monitoring of

blood pressure and renal function (use of aspirin concurrently with naproxen may

need further assessment for clinical need).

39,40

p. 870

p. 871

Figure 43-2 Overview of pharmacologic therapy for treatment of osteoarthritis. (Adapted from multiple

references.)

11,12,14,18,30

CASE 43-2, QUESTION 2: What monitoring parameters would be appropriate for this pharmacologic

treatment recommendation for S.L.?

Many clinicians recommend checking a basic metabolic panel and complete blood

count with differential 2 to 4 weeks after starting NSAIDs in older patients.

Depending on the initial laboratory results, testing can occur every 3 to 4 months,

thereafter for the next year. The risk for GI adverse events decreases after 1 month,

but is always present. Liver function should be checked regularly during the first year

of treatment and periodically thereafter. Patients with significant comorbidities may

need more stringent follow-up and monitoring. Analgesic efficacy is best evaluated

using a consistent systematic assessment approach. If S.L. is to remain on chronic

NSAID therapy, then monitoring her liver and renal function every 3 months for the

first year would be reasonable.

CASE 43-2, QUESTION 3: One week later after starting naproxen 500 mg twice daily, S.L. has been

adherent with therapy and had a basic metabolic panel completed before this office visit. S.L. reported a

decrease in pain since she had been started on naproxen. Laboratory values and vital signs obtained at this visit

include the following:

BP, 155/78 mm Hg

HR, 88 beats/minute

Height, 66 inches

Weight, 194 pounds

BMI, 30.7 kg/m

2

Sodium, 135 mEq/L

Potassium, 5.5 mEq/L

BUN, 40 mg/dL

Creatinine, 2.2 mg/dL

RBC, 4.7 × 10

6

/μL

Hemoglobin, 10.3 g/dL

Hematocrit, 33.8%

What changes, if any, need to be made with her OA therapy?

Gastrointestinal ulceration and bleeding remain a cardinal concern when

evaluating patients for treatment of chronic pain in OA. The addition of a PPI to a

nonselective NSAID has been proposed as a less expensive alternative to the more

expensive COX-2 inhibitor agent, celecoxib. Older patients with OA have

comorbidities requiring aspirin in addition to a COX-2 or NSAID. Goldstein et al.

41

compared celecoxib and aspirin with naproxen, lansoprazole, and aspirin with

endoscopically diagnosed ulcers after 12 weeks of therapy. Gastrointestinal

ulceration rates were found to be statistically insignificant among groups. In contrast,

another randomized controlled trial compared celecoxib with diclofenac and

omeprazole in patients with OA and rheumatoid arthritis for 6 months. The risk for

GI bleeding was evaluated across the small bowel.

42

There were less lower and upper gastrointestinal events in the celecoxib treatment

group. Consideration of clinically significant anemia not responsive to acidsuppressive interventions (PPIs) distal to the duodenum may provide the clinician

with more evidence in patients at increased risk for GI ulceration and bleeding. The

results are suggestive of better clinical outcomes with celecoxib versus diclofenac

and omeprazole.

42 These results are interesting because they contrast with results

found in previous studies. Additionally, it is unknown whether the results found with

diclofenac can be extrapolated to naproxen or other NSAIDs. Clearly, further

investigation is warranted before changes in practice are suggested. A meta-analysis

based on epidemiologic studies illustrates the safety of celecoxib with regard to risk

for GI ulceration and bleeding. Additionally, NSAIDs with long half-lives and slowrelease formulations were found to demonstrate higher risks for GI events. Higher

relative risk (RR) for GI bleeding (>5) was associated with naproxen, indomethacin,

ketoprofen, ketorolac, and piroxicam, whereas a lower RR (<5) was found for

ibuprofen, diclofenac, celecoxib, meloxicam, rofecoxib, and aceclofenac.

43

The most frequent reason for withdrawal from this year-long trial was GI adverse

events for both medications; however, abnormal liver function tests caused more

patients taking diclofenac to withdraw from the study.

42 Diclofenac is associated with

elevations in alanine aminotransferase and aspartate aminotransferase levels;

however, increases in aminotransferase levels alone are not predictive of liver

injury. The FDA recognizes increases in both bilirubin and aminotransferase levels

as surrogate markers for drug-induced liver disease. In a study completed by Laine et

al.,

44

the risk of hospitalization associated with diclofenac therapy is described as

relatively rare (0.023% per 100,000 patient-years). The low rate of hospitalization

may be secondary to clinical vigilance. This study also found elevations in liver

function test concentrations to occur in the initial 4 to 6 months of therapy and does

not necessarily parallel clinical significant liver injury.

p. 871

p. 872

Table 43-3

Recommendations for Nonpharmacologic and Pharmacologic Treatments by OA

Site

14

OA Site Nonpharmacologic Recommendations Pharmacologic Recommendations

Hand Evaluate ability to perform ADLs

Instruct in joint protection techniques

Provide assistance devices, as needed, to help

patients perform ADLs

Instruct in use of thermal agents for relief of

pain and stiffness

Provide splints for patients with

trapeziometacarpal joint OA

Topical capsaicin

Topical/oral NSAIDs, including trolamine

salicylate and COX-2 selective inhibitors

(patients ≥75 years should use topical

NSAIDs)

Tramadol

Discourage

Intra-articular therapies (corticosteroids,

hyaluronates)

Opioid analgesics

Knee Participate in aerobic and/or resistance

land-based exercise

Participate in aquatic exercise

Lose weight (if overweight)

Participate in self-management programs ±

psychosocial interventions

Use thermal agents and manual therapy in

Acetaminophen

Oral/topical NSAIDs

Patients ≥75 years should use topical

NSAIDs

Patients with h/o upper GI ulcer should use

COX-2 selective inhibitor or nonselective

NSAID + PPI

combination with PT-supervised exercise

Use medially directed patellar taping

Participate in tai chi programs

Receive walking aids, as needed

If lateral compartment OA, wear medially

wedged insoles

If medial compartment OA, wear laterally

wedged subtalar strapped insoles

Some moderate–severe pain patients are

candidates for acupuncture or TENS

Patients with upper GI bleed ≤1 year ago

should use COX-2 selective inhibitor + PPI

Tramadol

Intra-articular corticosteroid injections

Opioids or duloxetine for patients who failed

all other therapies and are not candidates for

total joint arthroplasty

Discourage

Chondroitin sulfate

Glucosamine

Topical capsaicin

Hip Participate in cardiovascular and/or

resistance land-based exercise

Participate in aquatic exercise

Lose weight (if overweight)

Participate in self-management programs ±

psychosocial interventions

Use thermal agents and manual therapy in

combination with PT-supervised exercise

Receive walking aids, as needed

Acetaminophen

Oral NSAIDs

Tramadol

Intra-articular corticosteroid injections

Opioids for patients who failed all other

therapies and are not candidates for total joint

arthroplasty

Discourage

Chondroitin sulfate

Glucosamine

TRAMADOL AND OPIOIDS

In the week that has passed, there has been an increase in potassium, serum

creatinine, and BUN. COX-2 preferential and nonselective inhibitors have the same

potential to cause adverse renal effects. Naproxen should be discontinued, and

additional monitoring should be ordered to ensure laboratory values return to

baseline. The drop in hemoglobin may also be concerning, and appropriate follow-up

with either endoscopy or stool occult blood testing should be considered.

CASE 43-2, QUESTION 4: S.L. has seen commercials on television advertising “knee injections.” Describe

the available therapeutic options.

In many patients with contraindications or subtherapeutic response to

acetaminophen, NSAIDs, or COX-2 inhibitors, a trial of tramadol should be

considered. Therapeutic alternatives for analgesia are now limited to opioids or

tramadol for S.L. Tramadol is a centrally acting analgesic that binds to the mu-opioid

receptor and also inhibits the uptake of norepinephrine and serotonin.

45 The ACR

recommends tramadol in those patients who have failed or have contraindications to

NSAIDs.

14 Tramadol should not be used in patients with a history of seizures or

receiving medications with serotonergic activity and requires dose adjustment with

diminished renal function.

45,46 Tramadol can be used with acetaminophen, and the

combination can be therapeutic.

47 However, she is taking citalopram for depression,

and there is a potential drug interaction with tramadol; therefore, this combination

should be judiciously considered. Opioid/acetaminophen combinations may be a

short-term option in the interim while S.L. is being evaluated for intra-articular

injection of either corticosteroid or viscosupplementation (hyaluronic acid injection)

by her physician.

In patients in whom the use of tramadol is ineffective or contraindicated, the use of

an opioid or opioid/acetaminophen combination can be considered.

48 Side effects

from opioids include constipation, confusion, hallucinations, respiratory depression,

tolerance, and addiction. A recent Cochrane review evaluated the use of oral and

transdermal nontramadol opioids in the treatment of OA of the hip and knee.

49

Although the findings did conclude opioids are effective, their modest benefits are

outweighed by their side effect profiles and should thus be avoided. Randomized,

placebo-controlled studies have pointed to the efficacy and tolerability of

transdermal buprenorphine with or without concurrent acetaminophen in the treatment

of hip or knee OA, although long-term safety cannot be concluded at this time.

50,51

DULOXETINE

Duloxetine, a serotonin and norepinephrine reuptake inhibitor, has been approved for

the treatment of chronic musculoskeletal pain,

p. 872

p. 873

in addition to several other indications. In a 13-week randomized, double-blind,

placebo-controlled trial involving 231 patients, duloxetine demonstrated statistically

significant reductions in osteoarthritic pain of the knee.

52 The magnitude of difference

in average pain between duloxetine and placebo in the reported mean end points and

the mean change from baseline was modest, yet the tolerability and adverse effect

profile of this medication are preferable to other potential treatment modalities. S.L.

is currently receiving citalopram for the treatment of major depressive disorder. The

risk-to-benefit analysis of switching citalopram to duloxetine has many

considerations. The treatment of the depression and the significant medical history of

the patient need to be carefully assessed. S.L. has a past medical history of recurrent

depression resistant to several different medications and has been stable for the last

year on citalopram. Next, tolerability and cost need to be evaluated because

duloxetine may have a higher copay than citalopram, despite both agents’ availability

as a nonbranded product. Should S.L. be switched to duloxetine for treatment of OArelated pain and depression, she should be counseled on the risk for transient

headaches, nausea, and less frequently diarrhea. Liver transaminases are also

recommended for periodic monitoring. Specific education regarding expected

treatment results should also be provided because the onset of analgesia with

duloxetine may be delayed following initiation. Given her concurrent diagnosis of

depression, her mood should be reassessed frequently during the transition.

Intra-Articular Therapy

Ultimately, many patients fail oral or topical therapies, and intra-articular (IA)

injections represent the last conservative efforts before surgical intervention for OA

of the knee. Aspiration of synovial fluid and injections of glucocorticoids or

viscosupplementation of hyaluronic acid are strategies that have been offered to

patients with severe knee OA. Injections of triamcinolone or methylprednisolone

with lidocaine 1% have been shown to be effective for approximately 4 to 8 weeks.

Typically, IA glucocorticoids are given no more frequently than every 3 months. Side

effects include a paradoxical localized inflammatory reaction.

53

In a small multicenter, randomized trial, the safety and efficacy of IA treatment

with hyaluronic acid in OA of the knee was demonstrated. However, there was a

rather large placebo response and a small effect size with treatment in this trial.

54

In a

2005 meta-analysis, intra-articular hyaluronic acid supplementation did not

demonstrate clinical efficacy in OA of the knee.

55

In contrast, a more recent Cochrane

review found intra-articular injection of hyaluronic acid products to be effective and

provide more sustained clinical effects than intra-articular injections of

glucocorticoids. The authors acknowledged considerable product variability and

corresponding times to clinical response.

56 A 2009 multicenter, randomized,

placebo-controlled trial did not find any efficacy of hyaluronic acid in hip OA.

57 A

meta-analysis reviewed studies of both intra-articular corticosteroids and hyaluronic

acid in the treatment of OA of the knee. Seven studies including 606 subjects were

included. Results suggest IA corticosteroids are comparatively more effective from

baseline to week 4, after which IA hyaluronic acid appears to have greater durability

of effect.

58

CASE 43-2, QUESTION 5: Two years have passed, and S.L. has now failed all conservative strategies

including intra-articular injections into her knee. After discussing all of her options with her physician, S.L. is

referred to an orthopedic surgeon for elective left total knee replacement. She is awaiting discharge from the

acute care hospital, pending transfer to a short-term rehabilitation facility to facilitate her return to home, and

resumption of her previous level of function. S.L.’s current medications are metoprolol succinate 50 mg daily,

lisinopril 20 mg daily, citalopram 20 mg daily, enoxaparin 30 mg subcutaneously twice daily, oxycodone CR 10

mg every 12 hours, senna/docusate one tablet twice daily, and oxycodone/acetaminophen 5 mg/325 mg one

tablet every 4 hours as needed for moderate pain and two tablets every 4 hours as needed for severe pain. S.L.

asks you, as the counseling pharmacist, why she still needs “shots in the belly?”

The American College of Chest Physicians (ACCP)’ highest level of evidence for

elective knee arthroplasty recommends low-molecular-weight heparin, fondaparinux,

dabigatran, apixaban, rivaroxaban or warfarin (international normalized ratio [INR]

goal of 2.5) for patients in whom a risk for significant bleeding does not exist. A

minimal duration of therapy is for 10 days after surgery and up to 35 days for some

patients.

59

It is important to educate S.L. with this information, providing the reason

for enoxaparin is to prevent blood clots in her legs or lungs. In cases in which the

creatinine clearance is less than 30 mL/minute, the appropriate dosage of enoxaparin

would be 30 mg subcutaneously once daily.

60

CASE 43-2, QUESTION 6: How long will S.L. need oxycodone CR and oxycodone/acetaminophen therapy?

Patients typically need the sustained-release dosing of their opioid analgesic given

on a routine schedule only while undergoing aggressive physical and occupational

therapy immediately after orthopedic surgery. By the time most patients return to their

home environments, the use of as-needed dosing of opioid/acetaminophen

combinations may be necessary for the completion of the short-term rehabilitation

process. However, the long-term use of opioids in the treatment of chronic pain

should be discouraged unless the benefits greatly outweigh the risks.

Comorbid Conditions in the Elderly

CASE 43-3

QUESTION 1: L.P. is a 76-year-old woman who was recently admitted to the hospital for elective right total

hip replacement. She had failed all previous conservative interventions. Her medical history is significant for

type 2 diabetes, hypertension, dyslipidemia, OA left knee and right hip, a right knee replacement 2 years ago,

coronary artery disease, and history of myocardial infarction 1 year ago. Medications include glipizide 10 mg

daily in the morning before breakfast, metformin 850 mg twice daily, lisinopril 20 mg daily, atorvastatin 40 mg

daily, metoprolol succinate 100 mg daily, rivaroxaban 10 mg once daily with dinner, aspirin 81 mg once daily,

celecoxib 200 mg once daily, and oxycodone/acetaminophen 5 mg/325 mg one tablet every 4 hours as needed

for right hip pain. Identify L.P.’s risks associated with COX-2 inhibitor use.

The risks associated with nonselective NSAID or COX-2 inhibitor use in older

adults with comorbid coronary artery disease include increased blood pressure, heart

failure, and worse cardiovascular outcomes. Additionally, diminished renal function

and gastrointestinal bleeding risks are relevant and require careful follow-up and

monitoring. The lowest effective nonselective NSAID or COX-2 inhibitor dose for

the shortest duration would possibly be recommended in situations where continued

therapy is clinically indicated.

CASE 43-3, QUESTION 2: Identify any drug–drug interactions that would be clinically significant relative to

L.P.’s prophylaxis for deep vein thrombosis after hip replacement surgery.

p. 873

p. 874

Caution is encouraged when combining medications to rivaroxaban that may

increase the risk of bleeding.

61

In this case, LP requires aspirin for cardiovascular

protection after the myocardial infarction. Additionally, celecoxib was added for

pain management following hip replacement surgery. The addition of antiplatelet

agents and NSAIDs to oral anticoagulant therapy increases the risk for bleeding. A

careful evaluation of the risks and benefits of combination therapy would suggest

discontinuation of the COX-2 inhibitor.

Dietary Supplements

Dietary supplements offer patients an alternative to prescription medications. Some

patients often either fail multiple prescription drugs or have intolerable side effects.

Others confuse dietary supplements with natural products and consider them safer

than traditional medications. In the case of OA, the role of glucosamine, chondroitin,

and the combination products has represented such an alternative to many patients.

As with any OTC dietary supplement, the vigor of product consistency and

standardization are not equal to FDA requirements for legend drugs. Researchers

have found in evaluating the use of glucosamine, chondroitin, and the combinations in

OA of the knee that they were all ineffective in reducing pain. However, it is worth

noting that treatment effects were more pronounced in the subgroup of patients with

moderate-to-severe reports of pain. Also, this trial included a celecoxib treatment

group that also did not reach statistical significance with regard to primary outcomes

measured.

62 Similar findings were published, concluding the lack of efficacy with

glucosamine in treatment of OA of the hip as well as degenerative lumbar OA.

63–65

More recently, in a double-blind, multicenter trial, the combination of glucosamine

and chondroitin was compared with celecoxib in patients with osteoarthritis of the

knee.

66 The results of this trial in approximately 600 patients demonstrated

noninferiority of the glucosamine with chondroitin compared to celecoxib after 6

months for the primary outcome of reduced pain.

Nontraditional alternatives for the pain, stiffness, and discomfort of OA are few

and certainly lack the vigor of large-scale, long-term, clinical trials. However, in

selected patients who wish to try glucosamine/chondroitin, a time-limited trial can be

considered in patients who fail or refuse more traditional approaches to

pharmacologic management. However, a general recommendation cannot be made for

all patients.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Fernandes L et al. EULAR recommendations for the non-pharmacological core management of hip and knee

osteoarthritis. Ann Rheum Dis. 2013;72(7):1125–1135. (17)

Lanza FL et al. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol.

2009;104:728. (30)

McAlindon TE et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis

Cartilage. 2014;22(3):363–388. (11)

Hochberg MC et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic

and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken).

2012;64(4):465–474. (14)

Key Website

Centers for Disease Control and Prevention. Osteoarthritis.

http://www.cdc.gov/arthritis/basics/osteoarthritis.htm. Accessed May 18, 2015. (1)

COMPLETE REFERENCES CHAPTER 43

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