Pain Management

Acute Pain In Cats: Treatment With NSAIDs

Acute Pain In Cats: Treatment With NSAIDs
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B. Duncan X. Lascelles, BSc, BVSc, CertVA, PhD, MRCVS, DSAS (ST), Diplomate ECVS & ACVS
North Carolina State University

The 5 important characteristics of an ideal NSAID for use in cats are described in this article, the second of a 2-part series. The author provides guidance on treating acute pain in cats with NSAIDS currently on the market, including recommended dosages.


At some point in a cat’s life, it will most likely suffer from pain related to an injury, disease, or surgery, and veterinarians have a duty to try to alleviate this pain. In the January/February 2014 issue of Today’s Veterinary Practice, Dr. Sheilah Robertson addressed the challenges of acute pain assessment in cats. However, deciding how to effectively treat this pain presents its own difficulties.

Pain in cats—both acute and chronic—is difficult to treat because cats:

  • Metabolize some drugs more slowly than dogs, potentially increasing the risk of adverse drug reactions1-3
  • Are prone to a gradual decline in renal function; one recent study found that up to 50% of cats may have chronic kidney disease4
  • Can be difficult to medicate and often resist administration of oral medication
  • Often do not show obvious outward signs of pain or illness, making evaluation of medication efficacy a challenge, especially in stoic cats5
  • Have a limited number of options when it comes to veterinary approved pain medications.

NSAIDs are one of the most common drug classes used to treat pain, and there is a robust body of information indicating that NSAIDs are effective in treating acute pain in cats.6,7 They have antipyretic, analgesic, and anti-inflammatory properties, which make them appealing therapeutic options; however, remember that there is not, and never will be, a completely safe NSAID for use in cats.

IS THERE AN IDEAL NSAID FOR USE IN CATS?

Based on our current understanding and the information available, if we were to design an ideal NSAID for use in cats, it would have certain important characteristics (Table 1).

Table 1. Characteristics of an Ideal NSAID for Use in Cats

1. Spares COX-1 and targets COX-2

2. Provides targeted action

  • Prolonged action in targeted tissues
  • Appropriate duration of action in the central nervous system
  • Spares ‘non target’ tissues

3. Can be administered with ease and accuracy

  • Injectable and oral forms available, which are interchangeable
  • Simple dose determination and titration
  • Palatable and easy-to-administer oral form

4. Displays wide safety margins and evidence-based clinical safety in target population

  • Toxicity studies demonstrate a wide safety margin in cats
  • Appropriately safe in the target population (eg, cats undergoing elective surgeries)

5. Demonstrates robust evidence of clinical efficacy

  • Effective for acute and postoperative pain control
  • Effective for alleviation of prolonged, maladaptive pain associated with chronic diseases

1. Spares COX-1 & Targets COX-2

NSAIDs work by inhibiting the production of prostaglandins (see The Role of Prostaglandins) from arachidonic acid by the enzyme cyclooxygenase (COX). There are 2 forms of the COX enzyme:

  • COX-1: Generally constitutive and involved in production of prostaglandins that protect gastric mucosa and maintain normal platelet function and renal perfusion
  • COX-2: Generally induced during inflammation and plays a role in healing and pain signaling;8 however, its activity also produces prostanoids involved in the normal function of certain tissues, such as the kidneys, brain, and reproductive system.

The ideal NSAID strikes a balance between COX-1 and COX-2 inhibition:

  • Nonselective COX inhibitors equally inhibit COX-1 and COX-2.9 These NSAIDs tend to be associated with classic NSAID side effects, such as gastrointestinal (GI) ulceration, anorexia, vomiting, diarrhea, and renal and liver toxicity.10
  • COX inhibitors that selectively inhibited COX-2 demonstrated a greater safety margin than nonselective COX inhibitors in initial studies in healthy humans. However, this greater safety margin does not hold true for humans at risk for GI side effects.11 Nothing is known about the relative risk of selective COX-2 inhibitors in veterinary medicine.
  • The ideal NSAID should, therefore:
    • Spare COX-1 as much as possible
    • Inhibit COX-2 sufficiently for efficacy against pain and inflammation
    • Spare enough COX-2 to allow it to function in normal everyday processes.

The Role of Prostaglandins

Prostaglandins are required for both everyday and compensatory functions of all organs and tissues. For example, prostaglandins are involved in GI protection and healing of GI ulcers as well as normal renal function and compensatory protective mechanisms of the kidney during hypovolemia.10 Prostaglandins are a predominant player in the production of pain in the periphery through sensitization of nerves. They are also involved in the processes of facilitation and amplification of noxious stimuli during central sensitization at the level of the dorsal horn of the spinal cord (Figure 1).12 Central sensitization has been shown, in veterinary species, to become established within 24 hours of a surgical procedure, and it contributes to postoperative pain and likely chronic pain.

Screen Shot 2015-06-18 at 11.02.04 AM

Figure 1. The role of prostaglandins in the periphery as sensitizers of pain fibers is well known. They are also involved in the facilitation and amplification of pain signals at various levels in the central nervous system; for example, central sensitization is assisted by prostanoids found in the dorsal horn of the spinal cord. Additionally, recent information suggests that locally produced prostanoids help decrease brain function in the areas involved in descending control over pain (endogenous analgesic systems).

2. Provides Targeted Action

Current thinking suggests that an ideal NSAID should have prolonged action at the site of inflammation and a short half-life in the central compartment, limiting exposure of normal, noninflamed, nonpainful tissues (Figure 2). This is because, given the broad distribution and role for prostaglandins throughout the body, if prostaglandins needed for normal, everyday functions are inhibited, there is potential for unwanted side effects.

Screen Shot 2015-06-18 at 11.02.15 AM

Figure 2. This figure illustrates the difference between 4 examples of NSAIDs, each dosed every 24 hours. All examples show tissue selectivity but have different half-lives. NSAID 1 has a short half-life, and is cleared quickly from the central compartment (blood), thus, theoretically limiting exposure of noninflamed tissues. In contrast, NSAID 4 has a relatively long half-life, exposing noninflamed tissues to the NSAID for most of the 24-hour period. The clinical significance of this difference between individual NSAIDs is not known.

Dr. Kay Brune, a leader in the field of NSAID research, has described a theory of “targeted tissue selectivity” that is a combination of enzyme specificity (selective COX-2 inhibition) and tissue selectivity, which, he has argued, might result in better toleration of the drug, while maintaining efficacy (see Concept of Tissue Selectivity).13

Concept of Tissue Selectivity

Tissue selectivity is a concept that involves the highly protein-bound nature of NSAIDs and the acidic environment of inflammation.

During the process of inflammation, there is extravasation, or leakage, of protein from blood vessels into the extracellular environment. Since NSAIDs are known to be “highly protein bound” at normal physiological pH, if an NSAID has been administered, it will be bound to this protein.

The acidic extracellular environment of the inflamed tissue causes dissociation of the drug from the protein due to the low pKa—acid dissociation constant—of the drug. After the drug dissociates from the protein, the increased free fraction of the active drug facilitates its movement into the cells where it then remains due to a phenomenon called ion trapping (passive movement of the drug into cells due to differences in pH between the intracellular and extracellular environment).13

This theory explains why NSAIDs may have a prolonged presence in inflamed tissue, while having a more rapid clearance from the central compartment—blood stream and other noninflamed organs.14

3. Administered with Ease & Accuracy

Ideally, for optimal practical administration, NSAIDs should be:

  • Available in an injectable and palatable, oral formulation
  • Easily titrated and have an easy-to-determine dose.

These 2 formulations should be usable and approved for use, interchangeably. For example, an injectable formulation facilitates both perioperative and immediate postoperative pain management, when it may be difficult or impossible to medicate animals orally. However, an oral formulation is beneficial for postoperative pain management upon discharge and long-term chronic pain management because it allows the drug to be administered in the home environment.

For cats specifically, palatable oral formulations facilitate administration and compliance—important components of pain management. Cats are selective about what they eat, and it is difficult to hide an unpalatable pill or medication in food or a treat, as is often done with dogs. If the cat won’t willingly take the medication, it must be restrained and dosed.

An NSAID formulation should be easily titrated, if necessary, and/or have an easy-to-determine dose. In tablet form, it should have a wide dose range that allows for administration of whole tablets, rather than fractioning tablets in order to stay within the therapeutic range.

4. Displays Wide Safety Margins & Evidence-Based Clinical Safety

First, toxicity studies of NSAIDs should demonstrate a robust and wide safety margin in healthy cats. No one has yet defined what a wide safety margin is, but veterinarians are encouraged to read the package inserts and Freedom of Information Summaries for the various NSAIDs.

Additionally, NSAIDs should have been evaluated and deemed to be appropriately safe in normal cats undergoing elective surgeries—the most common scenario for use of NSAIDs in general practice. Ideally, this information should be in the form of peer-reviewed literature, which gives the clinician a degree of comfort about the validity of the data.

Further, it would be ideal to have safety data in other target populations that would benefit from NSAID-induced pain relief, including cats with concurrent diseases, such as chronic kidney disease or cardiomyopathy.

5. Demonstrates Robust Clinical Efficacy

For feline acute pain, there should be robust evidence of clinical efficacy for the target problems, such as perioperative pain control. For feline chronic pain conditions, efficacy should be demonstrated for alleviation of prolonged, maladaptive pain associated with chronic disease in cats, such as degenerative joint disease, spinal pain, stomatitis, cystitis, and cancer. Until very recently, efficacy of NSAIDs was very difficult to measure, and there was little evidence they provided pain relief. A recent breakthrough in clinical study design, along with a Clinical Metrology Instrument, may now allow NSAIDs to be tested for efficacy in a wide variety of chronic diseases.15

Safe NSAID Use for Chronic Pain

With respect to chronic administration of NSAIDs, there is an urgent need for more safety data in older cats that:
1. Suffer from painful conditions requiring long-term pain management and
2. Have concurrent diseases, such as renal impairment, hyperthyroidism, and liver disease.

AVAILABLE NSAIDS FOR USE IN CATS

In the U.S., there are 2 FDA-approved NSAIDs for short-term use in cats: robenacoxib and meloxicam.16

Robenacoxib

Robenacoxib (Onsior, novartis.com) is FDA-approved for control of postoperative pain and inflammation associated with orthopedic surgery, ovariohysterectomy, and castration in cats.

It has high selectivity for the inhibition of COX-2, sparing COX-1.17 The clinical benefit of sparing COX-1 in the cat has not been demonstrated; however, benefits associated with COX-1 sparing in other species have been described.

Elegant work by Ludivig Pelligand at the Royal Veterinary College in the UK has demonstrated that robenacoxib has a very short half-life (3 hours) in the blood, yet persists, and is active, for at least 24 hours in inflamed tissue in cats,17 which demonstrates “tissue selectivity.”

Robenacoxib is approved for short-term administration (up to 3 days in the U.S.) in cats ≥ 4 months of age, weighing ≥ 5.5 lb (2.5 kg) (Table 2).6 In the U.S., robenacoxib is available in 6-mg, yeast-flavored tablets that can be taken with or without food. It should not be given in conjunction with any other NSAID or corticosteroids.

Meloxicam

Meloxicam (Metacam, us.boehringer-ingelheim.com) is FDA-approved for use in cats as a single, SC injection for postoperative pain. It is an example of a preferential COX-2 inhibitor that has greater inhibition of COX-2 than COX-1. Table 2 lists the recommended doses for meloxicam. Meloxicam is also considered tissue selective, but differs from robenacoxib in that it has a longer half-life and is, therefore, present in the central compartment longer.

Although the oral liquid suspension of meloxicam—approved for control of pain and inflammation associated with osteoarthritis in dogs—is not approved for cats, it has been used off-label for chronic pain management.

  • The 2010 Consensus Guidelines: Long-Term Use of NSAIDs in Cats (available at www.catvets.com/guidelines/practice-guidelines/nsaids-in-cats) provides recommendations from the International Society of Feline Medicine (ISFM) and American Academy of Feline Practitioners (AAFP) for long-term daily dosing of meloxicam oral suspension in cats.16
  • In addition to standard dosing protocols (Table 2), meloxicam has also been recommended at lower doses, such as 0.02 mg/kg/daily.18 At this dose, it is well tolerated, but there is currently no information on whether it is efficacious.19 However, a recent masked, placebo-controlled clinical study found a dose of 0.035 mg/kg to be efficacious over a 3-week period.15
Table 2. Recommended Doses: NSAIDs for Acute Pain Management in Cats
NSAID RECOMMENDATION SOURCE RECOMMENDED DOSE
Robenacoxib Recommended dose from manufacturer (FDA-approved) 1 mg/kg PO Q 24 H for 3 doses
Dose range, 1–2.4 mg/kg Q 24 H
Meloxicam
(injection)
Recommended dose from manufacturer (FDA-approved) 0.3 mg/kg SC (single injection)
Meloxicam
(oral suspension)*
Recommended dose from ISFM/AAFP for daily use14 0.1 mg/kg PO for 1 day;
then 0.05 mg/kg PO Q 24 H
Meloxicam
(oral suspension)*
Other recommendations18 0.05 mg/kg PO every other day or 0.025 mg/kg PO Q 24 H
* Not FDA approved for use in cats

In the U.S., the FDA issued a black box warning for meloxicam in 2010 (see Management of Chronic Pain in Cats, November/December 2012, at tvpjournal.com), indicating that repeated use of meloxicam in cats has been associated with acute renal failure and death. It is most likely that the combination of the higher perioperative dose and then follow-up dosing was responsible for these adverse events, but no details are available in the public domain.

AAFP = American Academy of Feline Practitioners; COX = cyclooxygenase; GI = gastrointestinal; ISFM = International Society of Feline Medicine; NSAID = nonsteroidal anti-inflammatory drug

References

  1. Lees P, Taylor PM. Pharmacodynamics and pharmacokinetics of flunixin in the cat. Br Vet J 1991; 147:298-305.
  2. Taylor PM, Delatour P, Landoni FM, et al. Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat. Res Vet Sci 1996; 60:144-151.
  3. Parton K, Balmer TV, Boyle J, et al. The pharmacokinetics and effects of intravenously administered carprofen and salicylate on gastrointestinal mucosa and selected biochemical measurements in healthy cats. J Vet Pharmacol Ther 2000; 23:73-79.
  4. Marino CL, Lascelles BD, Vaden SL, et al. Prevalence and classification of chronic kidney disease in cats randomly selected from four age groups and in cats recruited for degenerative joint disease studies. J Feline Med Surg 2013; epub ahead of print.
  5. Robertson SA. Managing pain in feline patients. Vet Clin North Am Small Anim Pract 2008; 38:1267-1290.
  6. King S, Roberts ES, Roycroft LM, et al. Evaluation of oral robenacoxib for the treatment of postoperative pain and inflammation in cats: Results of a randomized clinical trial. SRN Vet Sci 2012; doi: 10.5402/2012/794148.
  7. Carroll GL, Howe LB, Peterson KD. Analgesic efficacy of preoperative administration of meloxicam or butorphanol in onychectomized cats. JAVMA 2005; 226:913-919.
  8. Warner TD, Mitchell JA. Cyclooxygenases: New forms, new inhibitors, and lessons from the clinic. FASEB J 2004; 18:790-804.
  9. Lees P, Landoni MF, Giraudel J, et al. Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest. J Vet Pharmacol Ther 2004; 27:479-490.
  10. Marino C, Lascelles BD, Vaden S, et al. The prevalence and classification of chronic kidney disease in a randomly selected group of cats and in cats with degenerative joint disease. J Feline Med Surg 2013; epub ahead of print.
  11. Hsiang KW, Chen TS, Lin HY, et al. Incidence and possible risk factors for clinical upper gastrointestinal events in patients taking selective cyclooxygenase-2 inhibitors: A prospective, observational, cohort study in Taiwan. Clin Ther 2010; 32:1294-1303.
  12. Eisenach JC, Curry R, Rauck R, et al. Role of spinal cyclooxygenase in human postoperative and chronic pain. Anesthesiology 2010; 112:1225-1233.
  13. Brune K, Furst DE. Combining enzyme specificity and tissue selectivity of cyclooxygenase inhibitors: Towards better tolerability? Rheumatology (Oxford) 2007; 46:911-919.
  14. Brune K. Persistence of NSAIDs at effect sites and rapid disappearance from side-effect compartments contributes to tolerability. Curr Med Res Opin 2007; 23:2985-2995.
  15. Gruen ME, Griffith E, Thomson A, et al. Detection of clinically relevant pain relief in cats with degenerative joint disease associated pain. J Vet Intern Med 2014; 28:346-350.
  16. Sparkes AH, Heiene R, Lascelles BD, et al. ISFM and AAFP consensus guidelines: Long-term use of NSAIDs in cats. J Feline Med Surg 2010; 12:521-538.
  17. Pelligand L, King JN, Toutain PL, et al. Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation. J Vet Pharmacol Ther 2012; 35:19-32.
  18. Gowan RA, Lingard AE, Johnston L, et al. Retrospective case-control study of the effects of long-term dosing with meloxicam on renal function in aged cats with degenerative joint disease. J Feline Med Surg 2011; 13:752-761.
  19. Lascelles BD, Henderson AJ, Hackett IJ. Evaluation of the clinical efficacy of meloxicam in cats with painful locomotor disorders. J Small Anim Pract 2001; 42:587-593.

B. Duncan X. Lascelles

B. Duncan X. Lascelles, BSc, BVSc, CertVA, PhD, MRCVS, DSAS (ST), Diplomate ECVS & DACVS, is a professor in small animal surgery at North Carolina State University. He is director of the Comparative Pain Research Laboratory. His work on preemptive analgesia, opioid use in cats, perioperative NSAIDs, and outcome measures in canine osteoarthritis and feline degenerative joint disease has impacted veterinary medicine practice.

 

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>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' >Zimbabwe</option></select> <label for='input_6_10_6' id='input_6_10_6_label' 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