Orthopedics , Pain Management

Managing Chronic Pain in Dogs and Cats, Part 2: The Best of the Rest in the Management of Osteoarthritis

Managing Chronic Pain in Dogs and Cats, Part 2: The Best of the Rest in the Management of Osteoarthritis
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Mark E. Epstein, DVM, Diplomate ABVP (Canine/Feline), CVPP

In this article, the second of the 3-part series, Dr. Epstein discusses additional modalities for treating osteoarthritis in dogs and cats, including therapeutic exercise, polysulfated glycosaminoglycans, omega-3 fatty acids, and suggested off-label dose s for pain-modifying analgesic drugs.

Part 1The Two Most Important Tools in the Management of Osteoarthritis(November/December 2013, available at tvpjournal.com)—of this 3-part series addressed basic principles of chronic pain and also discussed treatment for its most common manifestation in companion animals: osteoarthritis (OA).

While Part 1 dealt with the 2 most important considerations in OA therapy: weight optimization and nonsteroidal anti-inflammatory drug (NSAID) therapy, this article discusses other modalities—both pharmacologic and nonpharmacologic—for treatment of canine and feline OA.

TOP 3 MODALITIES

Well-designed, systematic reviews evaluating treatment of OA and nonsurgical management of hip dysplasia in dogs are now available.1,2 Very good review articles are also available for cats diagnosed with OA.3

Based on these evidence-based perspectives—once weight optimization and NSAID therapy have been implemented—3 modalities rise to the top of the list.1.

1. Polysulfated Glycosaminoglycans

Veterinary polysulfated glycosaminoglycans (PSGAGs) administered by the parenteral route (ie, IV or IM injection) have met both regulatory scrutiny and quality control measures; independent studies appear to support their clinical utility.4,5 Examples include (Table 1):

  • PSGAG (Adequan Canine, novartis.com)
  • Sodium pentosan polysulfate (Cartrophen Vet for Dogs, biopharmaus.com.au).

In contrast, clinical evidence for oral nutraceuticals is limited in dogs and cats and, at best, conflicting in humans. However, it can be argued that initiating use of oral nutraceuticalsearly in life, particularly for at-risk breeds, is safe and may provide some long-term chondroprotective effect.

If nutraceuticals and oral supplements are used, caution is warranted due to the following concerns:

  • Degree of quality control
  • Potential drug interactions, especially with NSAIDs, because some over-the-counter products contain aspirin or other cyclooxygenase (COX)-inhibiting agents
  • Ingredients derived from endangered species
  • Need for clinical studies to demonstrate efficacy
TABLE 1. On- and Off-Label Use of Polysulfated Glycosaminoglycans
On-Label Dose: Dogs Off-Label Use Comments
Adequan 4.4 mg/kg IM twice weekly for 4 weeks
  • Dogs and cats
  • Administer SC
  • Continue on long-term basis, (eg, Q 1 month and adjust frequency according to patient needs)
Caution with patients at risk for bleeding dyscrasia
Cartrophen Vet 3 mg/kg SC Q 5—7 days, 4 times
  • Continue on long-term basis, (eg, repeat protocol Q 4—6 months)


2. Omega-3 Fatty Acids

Several randomized placebo-controlled blinded studies6-10 and one systematic review11have demonstrated the efficacy of diets rich in:12,13

  • Eicosapentaenoic acid (EPA) for dogs with OA
  • Docosahexaenoic acid (DHA) for cats with OA.

The availability of multiple randomized placebo-controlled blinded studies and systematic reviews place these data high on the evidence-based pyramid. However, this type of supplementation should be reserved for pets at a healthy weight.

Gate Theory of Pain

The spinal cord has a functional, neurophysiologic “gate” that can either block or allow pain signaling to the brain;16 by sending other signals to the brain during exercise (eg, proprioception), pain signaling through the spinal cord “gate” is, to a degree, blocked.

3. Therapeutic Exercise

While a relatively new modality in veterinary medicine, controlled, prescribed exercise is well established in humans for amelioration of pain related to OA. There is every reason to believe that dogs and cats can benefit as well due to a variety of mechanisms, including:

  • The Gate Theory of pain
  • Activation of endogenous opioids
  • Enhanced strength of periarticular soft tissue (eg, muscle, tendon, ligament) and resulting improved microstability of joints
  • Weight loss (if needed).

Some studies already support use of this modality in painful dogs with OA.14,15

ADDITIONAL OPTIONS

The evidence for other recommended treatments for OA pain is either limited, weak, conflicting, or based on in vitro cellular/molecular rather than clinical data. However, modalities that may play a role in management of OA in dogs and cats include:

  • Pharmacologic (pain modifying analgesic drugs)
  • Nonpharmacologic
  • Biologic.

Diagnostic & Treatment Considerations for OA Patients

  • Perform diagnostics.
  • Conduct a thorough history, physical examination, imaging, and laboratory evaluation.
  • Establish treatment goals with the owner, and then create the treatment plan.
  • Explain that the reward for the pet can be great in terms of longevity and improved quality of life, but only with good cooperation, compliance, and communication.
  • Educate owners on how to recognize potential drug adverse events. Explain what to do if adverse events occur.
  • Follow-up. Schedule the next reassessment before the client leaves. Touch base periodically with one of the validated chronic pain/disability owner assessment tools.

Pharmacologic Therapy Options (Table 2)

Gabapentin
No clinical studies evaluating gabapentin—as a single agent or an adjunct to NSAIDs—for the treatment of OA have been conducted in humans, dogs, or cats. However, a neuropharmacologic rationale exists for gabapentin’s ability to diminish central and peripheral sensitization, which is supported by a number of rodent studies.17,18

One canine study suggests that gabapentin may provide a chondroprotective effect in experimentally induced OA,19 and a pending study in cats appears to demonstrate the clinical efficacy of gabapentin for pain associated with naturally occurring feline hip OA.20

Macrostability: Gross subluxation
Microstability: Diminished laxity of joint that cannot be grossly appreciated

TABLE 2. Recommended Doses for Pain Modifying Analgesic Drugs
SUGGESTED DOSE PRIMARY ADVERSE EFFECTS & NOTES
Acetaminophen
10—15 mg/kg PO Q 12 H39
  • Contraindicated in cats
  • No special proclivity toward hepatotoxicity in dogs; judicious use recommended
Amantadine
NMDA receptor antagonist 
3—5 mg/kg PO Q 12 H21
  • Primary adverse effects include agitation and diarrhea
  • Anticholinergic
Amitriptylinea
Tricyclic antidepressant
Dogs, initial dose:
1—2 mg/kg PO Q 8—12 H39
Increase as needed to:
3—4 mg/kg PO Q 8—12 H29
  • Primary adverse effects include, in humans, dry mouth, sedation, behavioral changes, and seizure potentiation
Codeineb
Opioid
0.5—2 mg/kg PO Q 12 H39
  • Some suggest dogs only
  • Pharmacokinetics, but no clinical data, available
Gabapentin
Anticonvulsant
Initially 3—5 mg/kg PO Q 12 H, taper upwards to effect; doses as high as 20 mg/kg or more may be needed PO Q 8—12 H39
  • Primary adverse effects include somnolesense, which can be minimized by starting with lower doses and gradually increasing to effect
  • For smaller animals, may be compounded into 50 mg/mL nonxylitol containing suspension
Hydrocodoneb
Opioid
0.22—0.5 mg/kg PO Q 8—12 H39
  • Some suggest dogs only
  • Pharmacokinetics, but no clinical data, available
  • Primary adverse effects include sedation
Morphine/lidocaine/ketamine CRI
Dogs:
Morphine, 4 mcg/kg/min
Lidocaine, 50 mcg/kg/min
Ketamine, 10 mcg/kg/min
CRI for 24—48 H
  • Clinical utility for chronic pain holiday anecdotal only
  • Administer combined or individually
  • Primary adverse effects include, in humans, GI effects, behavioral changes, seizure potentiation, hypertension, bleeding dyscrasia, sedation
  • Unfavorable pharmacokinetics in dogs; better in cats
Tramadola
Cats:
1—4 mg/kg PO Q 12 H39
Dogs:
2—10c mg/kg PO Q 8—12 H29
  • No safety or toxicity data in dogs or cats; limited to no data to support efficacy in dogs
  • Higher doses may increase risk for adverse effects
Venflaxinea
SSNRI
3—4 mg/kg PO Q 8—12 H31
  • Not in clinical use for chronic pain in dogs or cats
  • No safety or toxicity data
  1. Caution should be exercised when using these and other serotoninergic, monoaminergic drugs in combination.
  2. If used in combination with acetaminophen, base dosage administered on calculated acetaminophen dose.
  3. Higher doses are more likely to lead to adverse effects, and it is prudent to initiate dosing at 2—4 mg/kg.
NMDA = N-methyl-D-aspartate; SSNRI = serotonin-norepinephrine reuptake inhibitor

Amantadine

One study in dogs with refractory OA demonstrated the efficacy of amantadine and an NSAID versus NSAIDs alone.21

Tramadol

The pharmacokinetics of oral tramadol do not favor its use for OA pain in dogs.22-25In fact, the pharmacokinetics of oral tramadol are not favorable in the dog, in general, and especially not for chronic use (plasma levels, low to begin with, diminish rapidly to near negligible levels after sequential use over several days). Even with IV tramadol, dogs do not produce the mu receptor active metabolite that occurs in humans.26 It may be better suited pharmacologically for cats,27 but its extremely bitter taste may limit its use.

At this time, no studies have been published that demonstrate tramadol’s efficacy for treatment of OA in cats or dogs, either alone or as an adjunct to NSAIDs. The results of one canine study suggested that dogs with OA improved with tramadol according to owner assessments; however, the placebo group also improved, and there was no improvement in the tramadol group according to objective gait analysis.25 However, one study submitted for publication may reveal more encouraging results.28

The Role of Constant Rate Infusions

Intravenous constant rate infusions (CRI) of ketamine, lidocaine, opioids, or a combination can be used for a 24 to 48 hour pain holiday and to also reduce central sensitization. Used for severe neuropathic pain states in humans, this methodology has been anecdotally used but not yet investigated in canine and feline patients with OA.


Tricyclic Antidepressants & Selective Serotonin/Norepinephrine Reuptake Inhibitors

Although known for their ability to treat chronic and neuropathic pain conditions in humans, as of yet, no data support the use of these drugs for management of canine or feline OA.

  • Duloxetine (Cymbalta, lilly.com), a selective serotonin/norepinephrine reuptake inhibitor, is labeled for musculoskeletal and low back pain in humans, but has very poor oral bioavailability in dogs.29
  • Oral venlafaxine (Effexor, pfizer.com), labeled as an antidepressant in humans, has been demonstrated to diminish pain intensity and improve function in humans with OA.30 In dogs, it has approximately 50% bioavailability and a half-life of 3 hours.31
  • There is no strong evidence for the pain modifying effect of fluoxetine, a selective serotonin reuptake inhibitor.

Corticosteroids

Intra-articular corticosteroid injection is a first-line therapy for OA in humans and horses. In dogs, studies in experimentally induced OA demonstrate that corticosteroid injections may have a disease modifying and, possibly, chondroprotective effect,32-35 but clinical studies are lacking.

Acetaminophen

Acetaminophen remains a first-line therapy for acute and chronic pain in elderly humans,36and unlike cats, a literature search for toxicity in dogs does not reveal any special sensitivity to adverse effects or toxicity in this species. Judicious use can be considered in dogs but not in cats.

Oral Opioids

Dogs have a robust first-pass effect with oral opioids, limiting their usefulness compared with human patients, but pharmacokinetic studies reveal the possible efficacy of codeine37and hydrocodone38 in this species.

Nonpharmacologic

Nonpharmacologic treatment of OA in dogs and cats includes a variety of therapies (Table 3). While unsupported at this time by strong clinical evidence, these modalities:

  • Have plausible, if yet unproven, beneficial effects
  • Are generally safe with proper use
  • May be employed as an adjunct to other therapies, or when nonpharmacologic modalities are indicated or preferred.

As part of an integrated approach to treating pain, acupuncture, in particular, has been accepted by both the National Institutes of Health (nih.gov) and International Veterinary Academy of Pain Management (ivapm.org) in their respective position/consensus statements.

Table 3. Common Nonpharmacologic Therapies for Canine & Feline OA
  • Acupuncture
  • Myofascial trigger point therapy
  • Therapeutic laser (photobiomodulation)
  • Pulsed acoustic wave therapy
  • Pulsed electromagnetic field therapy

Biologic

The relative merits and roles of intra-articular stem cell therapy, platelet-rich plasma therapy, extracellular matrix bioscaffolds, hyaluronate, and even botulinum toxin remain areas of interest and research. How these modalities will fit into management of OA remains undetermined at this time.

One commercial autologous conditioned serum product (IRAP, arthrexvetsystems.com) is labeled for intra-articular injection in horses with OA; it suppresses the highly pro-inflammatory cytokine Interleukin-1. There is no similar commercial product for use in dogs, but there is indication that the modality may have a disease-modifying effect in this species.41

A commercial systemically administered anti-nerve growth factor monoclonal antibody product is currently in development for the treatment of canine OA. Investigations are also in progress for treatment of canine OA with Interleukin-10, a potent inhibitor of spinal cord glial activity.

IN SUMMARY

The ideal pain management protocol for a particular OA patient will vary by stage of disease, doctor and client values, and of course, individual needs and responses.

COX = cyclooxygenase; CRI = constant rate infusion; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis; PSGAG = polysulfated glycosaminoglycan

 

READ MORE

Read Part 1 of this article, Managing Chronic Pain in Dogs and Cats (Osteoarthritis).

Read Part 3 of this article, Managing Chronic Pain (Nonosteoarthritic Pain Conditions).

References

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F04_BMark Epstein, DVM, Diplomate ABVP (Canine/Feline), CVPP, is the senior partner and medical director of Carolinas Animal Pain Management & TotalBond Animal Hospitals, a group of AAHA-accredited practices in the Charlotte and Gastonia, North Carolina, areas. He is a member of the American Academy of Pain Management and International Veterinary Academy of Pain Management, and a past president of the IVAPM and ABVP, and an author and lecturer on the recognition, prevention, and treatment of pain. Dr. Epstein received his DVM from the University of Georgia.

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aria-required="true"/> <label for='input_6_10_1' id='input_6_10_1_label' >Street Address</label> </span><span class='ginput_full address_line_2' id='input_6_10_2_container' > <input type='text' name='input_10.2' id='input_6_10_2' value='' /> <label for='input_6_10_2' id='input_6_10_2_label' >Address Line 2</label> </span><span class='ginput_left address_city' id='input_6_10_3_container' > <input type='text' name='input_10.3' id='input_6_10_3' value='' aria-required="true"/> <label for='input_6_10_3' id='input_6_10_3_label' >City</label> </span><span class='ginput_right address_state' id='input_6_10_4_container' > <input type='text' name='input_10.4' id='input_6_10_4' value='' aria-required="true"/> <label for='input_6_10_4' id='input_6_10_4_label' >State / Province / Region</label> </span><span class='ginput_left address_zip' id='input_6_10_5_container' > <input type='text' name='input_10.5' id='input_6_10_5' value='' aria-required="true"/> <label for='input_6_10_5' id='input_6_10_5_label' >ZIP / Postal Code</label> </span><span class='ginput_right address_country' id='input_6_10_6_container' > <select name='input_10.6' id='input_6_10_6' aria-required="true"><option value='' selected='selected'></option><option value='Afghanistan' >Afghanistan</option><option value='Åland Islands' >Åland Islands</option><option value='Albania' >Albania</option><option value='Algeria' >Algeria</option><option value='American Samoa' >American Samoa</option><option value='Andorra' >Andorra</option><option value='Angola' >Angola</option><option value='Anguilla' >Anguilla</option><option value='Antarctica' >Antarctica</option><option value='Antigua and Barbuda' >Antigua and Barbuda</option><option value='Argentina' >Argentina</option><option value='Armenia' >Armenia</option><option value='Aruba' >Aruba</option><option value='Australia' >Australia</option><option value='Austria' >Austria</option><option value='Azerbaijan' >Azerbaijan</option><option value='Bahamas' >Bahamas</option><option value='Bahrain' >Bahrain</option><option value='Bangladesh' >Bangladesh</option><option value='Barbados' >Barbados</option><option value='Belarus' >Belarus</option><option value='Belgium' >Belgium</option><option value='Belize' >Belize</option><option value='Benin' >Benin</option><option value='Bermuda' >Bermuda</option><option value='Bhutan' >Bhutan</option><option value='Bolivia' >Bolivia</option><option value='Bonaire, Sint Eustatius and Saba' >Bonaire, Sint Eustatius and Saba</option><option value='Bosnia and Herzegovina' >Bosnia and Herzegovina</option><option value='Botswana' >Botswana</option><option value='Bouvet Island' >Bouvet Island</option><option value='Brazil' >Brazil</option><option value='British Indian Ocean Territory' >British Indian Ocean Territory</option><option value='Brunei Darussalam' >Brunei Darussalam</option><option value='Bulgaria' >Bulgaria</option><option value='Burkina Faso' >Burkina Faso</option><option value='Burundi' >Burundi</option><option value='Cambodia' >Cambodia</option><option value='Cameroon' >Cameroon</option><option value='Canada' >Canada</option><option value='Cape Verde' >Cape Verde</option><option value='Cayman Islands' >Cayman Islands</option><option value='Central African Republic' >Central African Republic</option><option value='Chad' >Chad</option><option value='Chile' >Chile</option><option value='China' >China</option><option value='Christmas Island' >Christmas Island</option><option value='Cocos Islands' >Cocos Islands</option><option value='Colombia' >Colombia</option><option value='Comoros' >Comoros</option><option value='Congo, Democratic Republic of the' >Congo, Democratic Republic of the</option><option value='Congo, Republic of the' >Congo, Republic of the</option><option value='Cook Islands' >Cook Islands</option><option value='Costa Rica' >Costa Rica</option><option value='Côte d&#039;Ivoire' >Côte d&#039;Ivoire</option><option value='Croatia' >Croatia</option><option value='Cuba' >Cuba</option><option value='Curaçao' >Curaçao</option><option value='Cyprus' >Cyprus</option><option value='Czech Republic' >Czech Republic</option><option value='Denmark' >Denmark</option><option value='Djibouti' >Djibouti</option><option value='Dominica' >Dominica</option><option value='Dominican Republic' >Dominican Republic</option><option value='Ecuador' >Ecuador</option><option value='Egypt' >Egypt</option><option value='El Salvador' >El Salvador</option><option value='Equatorial Guinea' >Equatorial Guinea</option><option value='Eritrea' >Eritrea</option><option value='Estonia' >Estonia</option><option value='Eswatini (Swaziland)' >Eswatini (Swaziland)</option><option value='Ethiopia' >Ethiopia</option><option value='Falkland Islands' >Falkland Islands</option><option value='Faroe Islands' >Faroe Islands</option><option value='Fiji' >Fiji</option><option value='Finland' >Finland</option><option value='France' >France</option><option value='French Guiana' >French Guiana</option><option value='French Polynesia' >French Polynesia</option><option value='French Southern Territories' >French Southern Territories</option><option value='Gabon' >Gabon</option><option value='Gambia' >Gambia</option><option value='Georgia' >Georgia</option><option value='Germany' >Germany</option><option value='Ghana' >Ghana</option><option value='Gibraltar' >Gibraltar</option><option value='Greece' >Greece</option><option value='Greenland' >Greenland</option><option value='Grenada' >Grenada</option><option value='Guadeloupe' >Guadeloupe</option><option value='Guam' >Guam</option><option value='Guatemala' >Guatemala</option><option value='Guernsey' >Guernsey</option><option value='Guinea' >Guinea</option><option value='Guinea-Bissau' >Guinea-Bissau</option><option value='Guyana' >Guyana</option><option value='Haiti' >Haiti</option><option value='Heard and McDonald Islands' >Heard and McDonald Islands</option><option value='Holy See' >Holy See</option><option value='Honduras' >Honduras</option><option value='Hong Kong' >Hong Kong</option><option value='Hungary' >Hungary</option><option value='Iceland' >Iceland</option><option value='India' >India</option><option value='Indonesia' >Indonesia</option><option value='Iran' >Iran</option><option value='Iraq' >Iraq</option><option value='Ireland' >Ireland</option><option value='Isle of Man' >Isle of Man</option><option value='Israel' >Israel</option><option value='Italy' >Italy</option><option value='Jamaica' >Jamaica</option><option value='Japan' >Japan</option><option value='Jersey' >Jersey</option><option value='Jordan' >Jordan</option><option value='Kazakhstan' >Kazakhstan</option><option value='Kenya' >Kenya</option><option value='Kiribati' >Kiribati</option><option value='Kuwait' >Kuwait</option><option value='Kyrgyzstan' >Kyrgyzstan</option><option value='Lao People&#039;s Democratic Republic' >Lao People&#039;s Democratic Republic</option><option value='Latvia' >Latvia</option><option value='Lebanon' >Lebanon</option><option value='Lesotho' >Lesotho</option><option value='Liberia' >Liberia</option><option value='Libya' >Libya</option><option value='Liechtenstein' >Liechtenstein</option><option value='Lithuania' >Lithuania</option><option value='Luxembourg' >Luxembourg</option><option value='Macau' >Macau</option><option value='Macedonia' >Macedonia</option><option value='Madagascar' >Madagascar</option><option value='Malawi' >Malawi</option><option value='Malaysia' >Malaysia</option><option value='Maldives' >Maldives</option><option value='Mali' >Mali</option><option value='Malta' >Malta</option><option value='Marshall Islands' >Marshall Islands</option><option value='Martinique' >Martinique</option><option value='Mauritania' >Mauritania</option><option value='Mauritius' >Mauritius</option><option value='Mayotte' >Mayotte</option><option value='Mexico' >Mexico</option><option value='Micronesia' >Micronesia</option><option value='Moldova' >Moldova</option><option value='Monaco' >Monaco</option><option value='Mongolia' >Mongolia</option><option value='Montenegro' >Montenegro</option><option value='Montserrat' >Montserrat</option><option value='Morocco' >Morocco</option><option value='Mozambique' >Mozambique</option><option value='Myanmar' >Myanmar</option><option value='Namibia' >Namibia</option><option value='Nauru' >Nauru</option><option value='Nepal' >Nepal</option><option value='Netherlands' >Netherlands</option><option value='New Caledonia' >New Caledonia</option><option value='New Zealand' >New Zealand</option><option value='Nicaragua' >Nicaragua</option><option value='Niger' >Niger</option><option value='Nigeria' >Nigeria</option><option value='Niue' >Niue</option><option value='Norfolk Island' >Norfolk Island</option><option value='North Korea' >North Korea</option><option value='Northern Mariana Islands' >Northern Mariana Islands</option><option value='Norway' >Norway</option><option value='Oman' >Oman</option><option value='Pakistan' >Pakistan</option><option value='Palau' >Palau</option><option value='Palestine, State of' >Palestine, State of</option><option value='Panama' >Panama</option><option value='Papua New Guinea' >Papua New Guinea</option><option value='Paraguay' >Paraguay</option><option value='Peru' >Peru</option><option value='Philippines' >Philippines</option><option value='Pitcairn' >Pitcairn</option><option value='Poland' >Poland</option><option value='Portugal' >Portugal</option><option value='Puerto Rico' >Puerto Rico</option><option value='Qatar' >Qatar</option><option value='Réunion' >Réunion</option><option value='Romania' >Romania</option><option value='Russia' >Russia</option><option value='Rwanda' >Rwanda</option><option value='Saint Barthélemy' >Saint Barthélemy</option><option value='Saint Helena' >Saint Helena</option><option value='Saint Kitts and Nevis' >Saint Kitts and Nevis</option><option value='Saint Lucia' >Saint Lucia</option><option value='Saint Martin' >Saint Martin</option><option value='Saint Pierre and Miquelon' >Saint Pierre and Miquelon</option><option value='Saint Vincent and the Grenadines' >Saint Vincent and the Grenadines</option><option value='Samoa' >Samoa</option><option value='San Marino' >San Marino</option><option value='Sao Tome and Principe' >Sao Tome and Principe</option><option value='Saudi Arabia' >Saudi Arabia</option><option value='Senegal' >Senegal</option><option value='Serbia' >Serbia</option><option value='Seychelles' >Seychelles</option><option value='Sierra Leone' >Sierra Leone</option><option value='Singapore' >Singapore</option><option value='Sint Maarten' >Sint Maarten</option><option value='Slovakia' >Slovakia</option><option value='Slovenia' >Slovenia</option><option value='Solomon Islands' >Solomon Islands</option><option value='Somalia' >Somalia</option><option value='South Africa' >South Africa</option><option value='South Georgia' >South Georgia</option><option value='South Korea' >South Korea</option><option value='South Sudan' >South Sudan</option><option value='Spain' >Spain</option><option value='Sri Lanka' >Sri Lanka</option><option value='Sudan' >Sudan</option><option value='Suriname' >Suriname</option><option value='Svalbard and Jan Mayen Islands' >Svalbard and Jan Mayen Islands</option><option value='Sweden' >Sweden</option><option value='Switzerland' >Switzerland</option><option value='Syria' >Syria</option><option value='Taiwan' >Taiwan</option><option value='Tajikistan' >Tajikistan</option><option value='Tanzania' >Tanzania</option><option value='Thailand' >Thailand</option><option value='Timor-Leste' >Timor-Leste</option><option value='Togo' >Togo</option><option value='Tokelau' >Tokelau</option><option value='Tonga' >Tonga</option><option value='Trinidad and Tobago' >Trinidad and Tobago</option><option value='Tunisia' >Tunisia</option><option value='Turkey' >Turkey</option><option value='Turkmenistan' >Turkmenistan</option><option value='Turks and Caicos Islands' >Turks and Caicos Islands</option><option value='Tuvalu' >Tuvalu</option><option value='Uganda' >Uganda</option><option value='Ukraine' >Ukraine</option><option value='United Arab Emirates' >United Arab Emirates</option><option value='United Kingdom' >United Kingdom</option><option value='United States' >United States</option><option value='Uruguay' >Uruguay</option><option value='US Minor Outlying Islands' >US Minor Outlying Islands</option><option value='Uzbekistan' >Uzbekistan</option><option value='Vanuatu' >Vanuatu</option><option value='Venezuela' >Venezuela</option><option value='Vietnam' >Vietnam</option><option value='Virgin Islands, British' >Virgin Islands, British</option><option value='Virgin Islands, U.S.' >Virgin Islands, U.S.</option><option value='Wallis and Futuna' >Wallis and Futuna</option><option value='Western Sahara' >Western Sahara</option><option value='Yemen' >Yemen</option><option value='Zambia' >Zambia</option><option value='Zimbabwe' 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