Adjunctive Oral Analgesics: Targeting the peripheral and central nervous system
While NSAIDs are currently considered the foundation of oral pain management for dogs with OA, it is important to recognize that PGE2/EP4 (the target of NSAIDs) is only one of many factors involved in the transmission of pain. Additional therapies are used to target other pain mediators in the peripheral and central nervous system.
OA is the most common cause of chronic pain, and chronic pain is similar to and can include neuropathic pain. Neuropathic pain means that there are changes to the nervous system (neuroplasticity) that result in lowered pain thresholds. In other words, the nerves that previously just transmitted pain become the source of pain.
Below, we review different oral analgesics, including contraindications, side effects, and dosages.
Amantadine
Mechanism of action:
- Inhibition of NMDA receptors in the spinal cord. NMDA receptors play an important role in the generation of central sensitization, ie, the maladaptive changes that occur in the spinal cord due to repeated noxious stimuli from peripheral nerves. This is also known as neuroplasticity and the cause of neuropathic pain, including hyperalgesia and allodynia.
Evidence:
- A randomized, placebo-controlled clinical trial in dogs with OA that needed additional pain management beyond NSAIDs found that the addition of amantadine to Metacam resulted in significant improvement in client-specific outcome measures of activity compared to Metacam alone (placebo) (Lascelles BD, JVIM 2008). It is unknown whether amantadine provides analgesic effects alone or is only effective when combined with an NSAID, gabapentin or opioid.
Indications:
- Chronic pain (not considered effective for acute pain). Dogs with OA are likely to benefit from amantadine plus NSAID. It is unclear if amantadine is effective when used alone.
Contraindications/ Precautions:
- Safety studies have not been performed in dogs, but based on human data, use caution with the following: hepatic and renal disease, congestive heart failure, seizure disorders.
Side effects:
- Seizures reported with doses of 40-80 mg/kg for 2 years (toxicology studies in dogs). Specific safety studies have not been performed in client owned dogs, but there are reports of agitation, flatulence, loose stools/ diarrhea, particularly soon after starting the medication.
Dose (dogs):
- 3-5 mg/kg q 12-24 h
Gabapentin
Mechanism of action:
- Target A2delta-1 of voltage-gated Ca channel (VGCC) within the dorsal horn of the spinal cord; by interacting with this receptor, gabapentin prevents the release of the neurotransmitter glutamate. VGCC is upregulated when nerves are damaged (neuropathy), leading to increased release of neurotransmitters and thus the generation of neuropathic pain.
- NOTE: Gabapentin does NOT increase or decrease GABA
Evidence:
- There are pharmacokinetic studies and a few published reports evaluating gabapentin for post-surgical pain in dogs. Despite its widespread use, there are currently no clinical trials investigating gabapentin for the treatment of OA pain in dogs.
Indication:
- Chronic, neuropathic pain. Neuropathic pain likely develops in dogs with OA.
Contraindications/ Precautions:
- It is excreted by the kidneys; use caution/ decrease dose in dogs with significant renal insufficiency. Do NOT use the human brand label Neurontin oral solution as it contains xylitol (toxic to dogs).
- Antacids may reduce bioavailability; give 2 hours before or after administering antacids.
Side effects:
- Sedation and ataxia; consider slowly increasing the dose over days-weeks.
- When gabapentin is used to treat seizures in humans, weaning off the medication is recommended to prevent abrupt withdrawal-related seizures. It is not known whether weaning is needed in dogs when used for chronic pain, but a 1-week taper may be advisable after long term use.
Dose (dogs):
- 10-30 mg/ kg q 8 hours. Pharmacokinetic studies show that it should be dosed TID rather than BID in order for maximum efficacy. However, because sedation and ataxia are common at these doses, it is prudent to start at the low end of the dose given twice a day, then work up to TID dosing and higher doses as needed.
Pre-gabalin (Lyrica)
Mechanism of action:
- Similar to gabapentin
Evidence:
- One pharmacokinetic study in dogs; no clinical trials in dogs with OA.
Indication:
- As for gabapentin. In humans, this product is approved for the treatment of diabetic neuropathy and fibromyalgia. The potential benefit of pre-gabalin is improved bioavailability and longer half-life, allowing for twice a day dosing.
Contraindications/ Precautions:
- As for gabapentin. The cost of the brand name (Lyrica) has limited use of this medication in veterinary patients. Generic pre-gabalin is now available and more widespread use may be seen.
Side effects:
- As for gabapentin: sedation and ataxia; consider slowly increasing the dose over days-weeks. When used for chronic pain, but a 1-week taper may be advisable after long term use.
Dose (dogs):
- 4 mg/kg q 12 h- A primary advantage of pregabalin over gabapentin is BID dosing.
Tramadol
Mechanism of action:
- Tramadol is metabolized to over 30 metabolites. The metabolites O-desmethyltramadol (ODM) and N,O-didesmethyltramadol (DDM) are believed to be responsible for pharmacologic effects.
- Tramadol, or the metabolites, have effects on multiple receptors including mu opioid, norepinephrine and serotonin. ODM is primarily responsible for the mu opioid effects, and pharmacologic studies have shown that dogs do not produce a substantial amount of this metabolite. DDM may provide some weak mu-opioid effects, and tramadol (parent molecule) may work as a serotonin/ NE reuptake inhibitor.
- Repeated dosing of tramadol results in reduced absorption and bioavailability, with up to 70% reduction in plasma levels after 1 week of oral dosing in dogs.
Evidence:
- 2 studies of dogs with OA
- Malek S, et al. BMC Vet Res 2012: 4 mg/kg TID x 2 weeks—improvement in mobility (assessed by CBPI) vs. placebo; after 2 weeks, no detectable levels of tramadol in plasma of 4/ 11 dogs.
- Budsberg S, et al. JAVMA 2018: 5 mg/kg TID x 10 days—no significant improvement with force plate or CBPI
Indication:
- Not currently recommended for OA management in dogs based on poor long term bioavailability.
Contraindications/ precautions:
- Use caution in dogs with a history of seizures.
- Do not use concurrently with drugs that affect serotonin reuptake:
- MAO inhibitors (selegiline), tricyclic antidepressants (amitriptyline, clomipramine), SSRIs (fluoxetine) and SNRIs (venlafaxine, duloxetine).
- Use caution when combining with deracoxib postoperatively.
- May increase the risk of gastric ulceration/perforation when combined with SSRI/SNRI and NSAIDs.
- Co-administration of antacids is recommended if tramadol is combined with NSAIDs.
Side effects:
- Uncommon, may include sedation, restlessness, panting, nausea, anorexia, constipation, salivation, vomiting, tremors, convulsions
Dose (dogs):
- 4-10 mg/kg, q 8 h
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Methocarbamol
Mechanism of action:
- Muscle relaxant; can be helpful in acute and chronic inflammatory conditions. Myofascial pain is an important component of chronic arthritic pain. Peri-articular muscles are often atrophied with OA, yet they become fatigued through attempt at stabilizing the joint. This results in muscle spasticity and a pain-spasms-pain cycle. Paraspinal muscles are often affected with chronic OA of the limbs or spine.
- Works centrally at the level of the spinal cord on the internuncial neurons resulting in reduced skeletal muscle hyperactivity. Muscle tone is not changed.
Evidence:
Robaxin (Zoetis) is approved for use in dogs with IVDD, trauma causing muscular and ligamentous sprains, myositis, bursitis, synovitis, muscular spasm associated with surgery.
No studies specifically evaluating dogs with OA.
Indications:
Acute and Chronic pain of multiple etiologies, including OA
Side effects:
May cause sedation, salivation, vomiting, lethargy, weakness and ataxia. These effects are typically rare to mild at doses used for pain management.
Dose (dogs):
15-20 mg/kg PO q 8 hours.
Onset of action:
30 minutes to 2 hours.
Acetaminophen
Mechanism of action:
- Incompletely understood—believed to be a COX-3 inhibitor.
- COX-3 is a variant of COX-1 found in the central nervous system. It is only effective when inflammatory mediators are low, thus not believed to be a strong anti-inflammatory, but is an analgesic and anti-pyretic (fever reducer). It is not believed to interfere with platelet function.
- In humans, it is believed to modulate pain by lowering nitric oxide (NO) levels and activating serotonergic pathways; however, these mechanisms are not fully understood.
Evidence:
- No studies specifically evaluating dogs with OA; however, it has been used as a rescue analgesic (combined with codeine) in clinical trials.
Indication:
- Chronic pain, including OA
- Acute flares (rescue medication used in addition to NSAIDs or other medications)
- During washout period between medications
- Post surgery in dogs that do not tolerate NSAIDs
Contraindications:
- CATS!!!! DO NOT USE IN CATS!!!!!
- Not recommended for immediate post-operative use in dogs.
- Use caution in dogs with liver disease.
Side effects:
- Not fully understood, some risk for liver, kidney, GI adverse effects, though in humans, this medication is often well tolerated in those that experience GI upset with COX inhibiting NSAIDs.
Dose (dogs):
- 10-15 mg/kg q 8-12 hours; May start at doses up to 30 mg/kg TID for 3-5 days.
Codeine
Mechanism of action:
- Mu agonist. Pharmacokinetic studies in dogs have shown poor bioavailability- only 4% of the drug reaches systemic circulation.
- Dogs form high levels of the metabolite codeine-6-glucuronide which is believed to provide pain-relieving effects.
Evidence:
- There are no clinical studies investigating codeine for OA or chronic pain in dogs.
Indication:
- For mild to moderate pain. Also available as a formulation with acetaminophen.
- Also used to treat cough and diarrhea.
Contraindications/ Precautions:
- Oral opioids are not considered to be highly effective in managing chronic/OA pain. Codeine is a schedule II drug, and risk for diversion is high. Formulation with acetaminophen is class III, but still remains a high risk for diversion or abuse.
- DO NOT use acetaminophen formulation in cats.
- Use caution with concurrent use of MAOI (selegiline), dogs with hypothyroidism, severe renal insufficiency, Addisons, respiratory distress
Side effects:
- Sedation, constipation, respiratory depression
Dose (dogs):
- 0.5-2 mg/kg q 6-12 h
Amitriptyline:
Mechanism of action:
- This is a tricyclic antidepressant that may provide analgesia by enhancing descending inhibition at the level of the spinal cord (ie, increasing the natural actions that modulate pain). It is a serotonin-norepinephrine reuptake inhibitor and may also have activity at NMDA, opioid and other receptors as well having as anti-inflammatory effects by decreasing PGE2 and TNF-alpha production.
Evidence:
- A small case series (3 dogs) described the successful treatment of neuropathic pain in dogs with either amitriptyline or gabapentin (Cashmore RG, 2009). Human clinical trials have found effectiveness in people with neuropathic pain.
Indications:
- Behavior problems such as anxiety. Chronic, neuropathic pain, including chronic itching due to nerve injury.
Contraindications/ Precautions:
- Caution with use with some parasiticides (amitraz), seizures, diabetes, adrenal tumors, glaucoma, KCS, liver and heart disease.
Side effects:
- Sedation, constipation, dry mouth, seizures, hyperexcitability, arrhythmias, fever, urine retention, PU/PD, hypotension, bone marrow suppression.
Dose:
- 3-4 mg/kg twice a day
Venlafaxine
Mechanism of action:
- Serotonin/ norepinephrine reuptake inhibitors (SNRI); human brand name Effexor
Evidence:
- A pharmacokinetic study in dogs; no clinical trials in dogs with OA
Indications:
- Humans: Anti-depressant and treatment of chronic, neuropathic pain, chronic back pain, and OA.
- In dogs, has traditionally been used for behavior problems, but some clinicians are starting to explore using for chronic pain/ OA.
Contraindications/ Precautions:
- Use caution with other SSRI/SNRI and MAOIs.
Side effects:
- (Reported from accidental overdose of human product) Agitation, aggression, panting, sedation, tachycardia, salivation, vomiting, diarrhea, tremors, seizures (serotonin syndrome)
Dose:
- 3-4 mg/kg q 8-12 h
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