Guidelines on Anesthesia and Analgesia in Non-Human Primates

1. Principal Investigator: Responsible to ensure appropriate anesthesia and/or analgesia is provided for all non-human primates undergoing potentially painful procedures, including survival surgery, unless otherwise indicated in the relevant approved protocol.

1. Pre-Anesthetic Evaluation
   1. Research related considerations:
      1. Animals on food or water restriction should preferably have the restriction discontinued for 1-2 days prior to anesthesia.
      2. Cranial surgery often results in prolonged anesthetic time and additional considerations are needed.
         1. Drug selection should include drugs that decrease intracranial pressure.
         2. Staging placement of hardware and devices, along with pre-surgical imaging, can reduce overall procedural and anesthetic time.
2. Handling & Restraint
   1. Due to occupational health concerns, minimally invasive procedures which could be performed in conscious or minimally sedated animals are not safe in many non-human primates. Sedation or anesthesia is recommended.
   2. For some procedures such as blood collection, positive reinforcement training (PRT) to facilitate cooperation and acclimation to procedural techniques may provide an alternative to sedation
3. Pre-anesthetic Fasting
   1. Withhold food for at least 8 hours but no longer than 24 hours prior to sedation or anesthesia to reduce the risk of regurgitation and aspiration.
      1. Fasting for periods greater than 24 hours related to specialized procedures (i.e., gastrointestinal procedures) should be described in the protocol.
   2. Juveniles or small non-human primate species should only be fasted 4-6 hours to help avoid hypoglycemia.
   3. Do not withhold water prior to anesthesia or sedation.
   4. For neonatal or unhealthy animals, special care is required. Consult a ULAM Faculty Veterinarian prior to fasting these animals.
4. Apply sterile non-medicated ophthalmic ointment to the eyes to prevent corneal drying during anesthesia or sedation.
5. Intubation:
   1. Table 1: Recommended Endotracheal Tube Sizes Based on Weight 

ii. Intubation in NHPs can be challenging due to their head position relative to their upright posture and their short trachea. Difficulty with airway visualization and unilateral intubation are both concerns.

iii. Always auscultate for bilateral breath sounds after intubation using positive pressure ventilation to ensure correct tube placement.

iv. Contact the ULAM Training Core ([email protected] or 734-763-8039) if you need training in nonhuman primate intubation.

b. Vascular access

i. The cephalic vein of the forelimb or the saphenous vein of the hind limb are common sites for IV catheter placement. For more invasive catheterization with multilumen central lines, the femoral vein can be used.

ii. Intravenous fluids are recommended for full anesthetic procedures of 30 minutes or more. More information on intravenous fluid choices and rates can be found in Guidelines on the Performance of Surgery in Non-Rodent Mammals.

1. More information on anesthetic/sedation monitoring requirements can found in Anesthesia and Sedation Monitoring Guidelines.
2. The goal of monitoring should be to maintain normal cardiac function, respiratory function, and body temperature. Understanding the basic physiologic effects of the anesthetics used is paramount to correctly interpreting monitoring parameters. More information on anesthetic and sedative effects on physiologic parameters can be found in Anesthesia and Analgesia Drug Descriptions.
3. Blood Pressure:
   1. Under anesthesia, systolic blood pressure should remain above 90 mmHg. Mean blood pressure should remain above 60 mmHg.

Table 2: Vasopressors

• 1. d.
  Table 3: Physiologic Data of Macaques

• Normal physiologic values (temperature, respiratory rate, heart rate) will vary between species.
• Under anesthesia, normal respiratory rate and heart rate can be 10-20% lower than an unanesthetized animal.
• Hypothermia under sedation or anesthesia can compromise organ function and exacerbate the effects of inhalant agents. In small species primate speciess, it can be life threatening. Normal physiologic temperature should be maintained while under anesthesia. An external heat source should be provided during the entire anesthetic and recovery period to prevent hypothermia.
• For examples of approved external heat supplementation products, refer to Anesthesia and Sedation Monitoring Guidelines

1. More information on required monitoring parameters during post-operative recovery can be found in Guidelines on the Performance of Surgery in Non-Rodent Mammals and Anesthesia and Sedation Monitoring Guidelines.
2. Recover animals in their cage under supervision. Animals should be directly monitored until able to maintain a parent airway (swallow and cough) and sit up. Lay animals lateral to prevent potential aspiration during recovery.
3. Food and water should be withheld until the animal is fully recovered and ambulating normally.
4. Pair-housed animals should be reintroduced to their social group as soon as possible to avoid fighting upon reintroduction. Animals should be able to eat, drink, ambulate well, and respond to stimulation before reintroduction. This time is usually 6-24 hours after the animal sits up postoperatively.

1. Detailed information on all approved anesthetics and sedatives can be found in Anesthesia and Analgesia Drug Descriptions.
2. Extrapolation of doses between species should be avoided. For non-macaque species, please consult with a ULAM veterinarian.
3. Inhalants can be used with all of these combinations to extend duration or enhance depth of sedation/anesthesia.
4. Table 4: Single Agent Sedation Dosage Information
   

   Drug	Dosage and Routea	Duration	Notesa
   Dexmedetomidine	1-32 mcg/kg SC, IM 0.5-1 mcg/kg bolus for emergence delirium	20-30 min	Can cause bradycardia while appropriate cardiac output and blood pressure are maintained. Reversible with atipamezole.
   Ketamine	5-15 mg/kg IM (4-10 times IM dose if given PO) Smaller species 15-25 mg/kg Larger species 5-15 mg/kg	30 min	Moderate sedation, immobilization, some analgesia. No muscle relaxation. Bite reflex is lost but swallowing and laryngeal reflexes retained. Caution if risk of cerebral edema.

   ^aIntramuscular (IM), Intravenous (IV), Subcutaneous (SC)

5. Table 5: Sedation Dosage Information (Combination Agents)
   

   Drug	Multiple Species Dosea	Duration	Notes
   Ketamine/Dexmedetomidine	5-10 mg/kg ketamine IM 10-30 mcg/kg dexmedetomidine IM	30-40 min anesthesia 60-120 min sedation	Sedation to light surgical anesthesia
   Ketamine/Diazepam b	3-5 mg/kg ketamine IM 0.5-1 mg/kg diazepam IM	30-40 min anesthesia 60-90 min sedation	Light surgical anesthesia Diazepam reversible with flumazenil
   Ketamine/Midazolam b	5-15 mg/kg ketamine IM 0.05-0.3 mg/kg midazolam IMb	Immobilization, light to moderate sedation	Midazolam reversible with flumazenil.
   Midazolam/Dexmedetomidine	0.3 mg/kg midazolam IM 30 mcg/kg dexmedetomidine IM	75 +/- 40 min	Deep sedation to light anesthesia
   Butorphanol/Medetomidine	0.3 mg/kg butorphanol IM 0.03 mg/kg medetomidine IM		Adequate for intubation.
   Tiletamine/Zolazepam (Telazol®)	1-3 mg/kg IM 4-6 mg/kg IM	15 min in smaller primates. Up to 60 min in macaques and baboons.	Immobilization to deep sedation. Minimal cardiovascular depression, lower drug volumes. May cause marked hypothermia Caution if risk of cerebral edema.
   Alphaxalone/Dexmedetomidine	5 mg/kg alphaxalone IM 10 mcg/kg dexmedetomidine IM	50-60 min in macaques	Supplemental oxygen recommended
   Alphaxalone/Diazepam	5 mg/kg alphaxalone IM 0.5 mg/kg diazepam IM	50-60 min in macaques	Supplemental oxygen recommended

   ^aIntramuscular (IM), Intravenous (IV), Subcutaneous (SC)
   ^bDoes not allow intubation

1. Anticholinergics
   1. Can be utilized to treat or prevent bradycardia and hyper salivation.
   2. Table 6: Anticholinergics Dosage Information
      

      Drug	Dosage and Routea	Notesa
      Atropine	0.025-0.05 mg/kg IM, SC, IV	Half-life is 2 hours. Repeat doses at ½ calculated dose. Due to more rapid onset of action, recommended for emergent situations.
      Glycopyrrolate	0.005-0.010 mg/kg IM, SC, IV	Half-life is 4 hours. Repeat doses at ½ calculated dose.

       
      ^aIntramuscular (IM), Intravenous (IV), Subcutaneous (SC)

2. Table 7: Injectable Anesthetics for Use with Intubation
   1. For long duration procedures (x > 3 hours), total or partial intravenous anesthesia can greatly reduce the dose of inhalants to offset their severe hypotensive effects.
   2. Table 7
      

      Drug	Dosage and Routea	Notesa
      Propofol	2-8 mg/kg IV to effect CRI 18-24 mg/kg/h	10-20 minute duration; use a lower dose with premedication. Due to apnea, use with intubation and inject slowly for induction.
      Propofol/Fentanyl	2-10mg/kg/h Propofol CRI 5-10mcg/kg IV bolus followed by 2-5mcg/kg/h fentanyl CRI	Inhalant-sparing effects if used as partial or total intravenous anesthesia.
      Fentanyl	5-20 mcg/kg/h IV fentanyl CRI	Short duration of action necessitates CRI administration for efficacy. Fentanyl can be reversed with naloxone.
      Alphaxalone	1.0-3.0 mg/kg IV bolus 0.01-0.13 mg/kg/min CRI	Used for induction and maintenance of general anesthesia. Premed with diazepam (0.5-1.25 mg/kg), ketamine (2 mg/kg), or midazolam (0.05-0.1 mg/kg) IM. May cause apnea.

       
      ^aIntramuscular (IM), Intravenous (IV), Subcutaneous (SC)

3. Inhalation Anesthetics
   1. Table 6: Inhalation Anesthetic Dosage Information
      

      Drug	Dosage and Route	Notes
      Isoflurane	3-5% Induction 0.5-3% Maintenance	Recovery is fast and reversal of circulatory and respiratory depression is rapid when the inhaled concentration is reduced. Mask or chamber induction may cause airway irritation and distress. Ataxia can be seen in recovery.
      Sevoflurane	4-8% Induction 1.25-4% Maintenance	Excellent for mask induction because of the non-pungent smell. Not irritating to the respiratory tract. Because of the rapid recovery, use caution (and appropriate sedation) during the recovery phase.

Reversal agents can be useful to reduce prolonged recovery times or in the event of anesthetic complications. Analgesic effects are also reversed with the use of reversal agents, and pain management should be modified accordingly.

1. Table 8: Reversal Agents

b. Inhalation Anesthetics 

i. Table 9: Inhalation Anesthetic Dosage Information 

1. Extreme care must be taken to ensure that a proper level of anesthesia and analgesia is achieved prior to administering a neuromuscular blocking agent.
2. Neuromuscular blocking agents require special monitoring procedures which are detailed in Anesthesia and Sedation Monitoring Guidelines.
3. Concurrent positive pressure ventilation is required. Reversal of NMBAs with neostigmine and glycopyrrolate is possible under specific conditions. Consult the ULAM veterinarians for instructions on NMBA reversal.
4. Table 10: Neuromuscular Blocking Agent Dosage Information
   

   Drug	Dosage and Routea	Notesa
   Atracurium	0.25-0.3 mf/kg IV 1.5 mcg/kg/min	Continuous intravenous infusion can be used to maintain and repeated doses are not cumulative.
   Vecuronium	0.04-0.06 mg/kg IV	Does not induce tachycardia or histamine release.
   Pancuronium	0.08-0.1 mg/kg IV	Lasts longer than vecuronium and produces mild increases in blood pressure and heart rate.

   ^aIntravenous (IV)

1. Administer local anesthetic blocks cold to enhance vasoconstriction, extending the peripheral nerve block time and local effect.
2. The addition of dexmedetomidine 1-2 mcg/mL of local anesthesia solution can extend local anesthesia.
3. Table 11: Local Anesthetic Dosage Information
   

   Drug	Dosage and Routea	Onset and Duration	Notesa
   Lidocaine 1-2%	1-4 mg/kg tissue infiltration (toxic dose > 10 mg/kg other species)	Onset: 1-2 min Duration: 1.5-2 h	Can be diluted 1 in 2 to increase accuracy of dosing in smaller primates.
   Bupivacaine 0.25-0.5%	1-2 mg/kg tissue infiltration (toxic dose > 4 mg/kg other species)	Onset: 5-10 min Duration: 4-12 h	Cardio-toxic: aspirate prior to injection, do not give IV. Can be diluted 1 in 2 to increase accuracy of dosing in smaller primates.

   ^aSubcutaneous (SC)

1. Assessment of pain in primates can be challenging to recognize due to their stoic temperament and occupational health and safety concerns preventing close assessment of surgical sites.
2. Signs of Pain in Non-human Primates
   May include, but not limited to, the following:
   1. Persistent vocalizations
   2. Restlessness
   3. Lethargy
   4. Inappetence
   5. Ungroomed hair and coat
   6. Crouched posture
   7. Glassy eyes
   8. Social isolation
   9. Abnormal aggression
   10. Increased respiratory rate or effort
   11. Increased resting heart rate
   12. Reluctance to move
3. Prevention and Management of Pain
   Prevention of pain by administering analgesics prior to anesthetic recovery is more effective than treatment after signs have developed. Several analgesics are available.
   1. Primates experience nausea and vomiting secondary to anesthesia. Administration of pre-operative anti-nausea and/or anti-emetic medications eliminate or decrease post-operative nausea and vomiting.
   2. Table 12: Pre-operative anti-nausea and anti-emetic medications

1. d. Preemptive Analgesia

i. Particularly opioids like buprenorphine, can reduce the dose of anesthetics required for surgical anesthesia. In small primate species, there may be increased respiratory depression associated with anesthetics.
ii. When preemptive analgesia is used, consider reducing the dose of anesthetic (whether inhalant or injectable) to the low end of the recommended range.
iii. Anesthetic depth must be carefully monitored, and drug doses may need to be titrated to maintain appropriate levels.
iv. Please see the Policy On Analgesia in Animals Undergoing Surgery for guidance on analgesics used in various surgical procedures.

e. Table 13: NSAID Dosage Information

1. Drug	Dosage and Routea	Duration of Effect	Notes
   Carprofen (Rimadyl®)	2-4 mg/kg PO, SC, IM	24 h	Mild to moderate analgesia. Dosing frequency can be increased for 2-3 dosages if required. May can an increased risk of stomach ulcers.
   Meloxicam	Loading dose 0.2 mg/kg SC once followed by 0.1 mg/kg once a day for 2-3 days	24 h	Moderate analgesia. Only COX-2 selective for primates. May be given for up to 4-5 days if needed. Dosing frequency can be increased for 2-3 dosages if required. Low oral bioavailability so higher doses are needed if PO route considered.

   ^aIntramuscular (IM), Intravenous (IV), Subcutaneous (SC)

   f. Table 14: Opioid Dosage Information
   

   Drug	Dosage and Routea	Duration of Effect	Notes
   Buprenorphine (Buprenex)	0.005-0.03 mg/kg SC, IM, IV	6-12 h	Mild to moderate analgesia. Absorbed slowly (30 minutes to effect). Higher doses may lead to sedation and/or respiratory depression. Almost no sedation at lower doses. Cannot be effectively reversed. Useful to reverse mu agonist opioids while retaining analgesia.
   Buprenorphine, long-acting (Simbadol)	0.24 mg/kg SC every 2 days 0.72 mg/kg SC every 3 days for Old Worlds	48-72 h	Mild lethargy and pruritis can be seen with both doses
   Fentanyl	5-10 mcg/kg IV bolus followed by 2-5 mcg/kg/h CRI		Taper at end of surgery. Causes dose-dependent respiratory depression.
   Butorphanol	0.05mg/kg IM	8 h	Mild to moderate analgesia, no sedation or muscle relaxation. Can work synergistically with other injectables to prolong recovery.

   ^aIntramuscular (IM), Intravenous (IV), Subcutaneous (SC)

1. In the event of an anesthetic crisis, turn anesthetic gases off and contact a ULAM veterinarian at 734-936-1037 immediately. Have emergency drugs and instruments in the surgery suite ready for use.
2. Reverse anesthetic agents, if appropriate.
3. Use the following guidelines to support the animal until the veterinarian arrives:
   1. A – Ensure a patent Airway: Place a cuffed endotracheal tube or confirm patency of tube already in place. If an endotracheal tube is not available, use a face mask to ventilate.
   2. B – Assist in Breathing if necessary: Turn anesthetic gases off and ventilate with pure oxygen. A rapid ventilation rate (> 20 breaths per minute) is recommended to remove carbon dioxide, prevent acidosis, and decrease cerebral pressure.
   3. C – Provide Cardiovascular Support as indicated: This can include rapid chest compressions (30-40% of lateral dimension; 80-120/minute) with the animal in lateral recumbency, and rapid infusion of intravenous crystalloid fluids (50-60 ml/kg bolus) to support perfusion.
   4. If no heartbeat can be heard or no pulses felt, then epinephrine should be given IV (see chart below). Reversal drugs should be given if opioids or xylazine have been used.

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