Intrathecal Drug Protocols: Medications and Dosing Guidelines

This educational resource synthesizes medication protocols from the SFETD Intrathecal Toolbox 2024 and Polyanalgesic Consensus Conference (PACC) 2017 recommendations.

First-Line Medication Protocols

PACC International Recommendations

According to the Polyanalgesic Consensus Conference 2017 international guidelines:

First Line:

Morphine + ziconotide
Morphine + bupivacaine

Second Line:

Morphine/fentanyl + bupivacaine + ziconotide

Third Line:

Ziconotide (monotherapy)
Morphine (monotherapy)
Morphine + clonidine
Morphine/fentanyl + bupivacaine + clonidine
Ziconotide + bupivacaine
Ziconotide + clonidine

French Practice Standards

As practiced in France according to SFETD guidelines:

First Line:

Morphine + local anesthetic (ropivacaine) + ziconotide
Morphine + local anesthetic (ropivacaine) if ziconotide unavailable

Note: The SFETD Toolbox emphasizes that ziconotide introduction is better tolerated when started early, as dose increases can be made very gradually. Prescribing also depends on compounding pharmacy availability and safe preparation capability.

Morphine: Primary Opioid Analgesic

Classification and Mechanism

Type: Competitive agonist of opiate receptors, primarily Mu, secondarily Kappa
Target: Direct action on spinal cord nociceptive pathways
Result: Blockage of perception of pain signals

Indications

Intense pain, especially nociceptive component
Cancer-related pain
Mixed pain syndromes (most common in oncology)

Initial Dosing

According to SFETD protocols:

Dose Conversion:

Intrathecal dose = 1/100 of IV daily dose
Intrathecal dose = 1/300 of oral daily dose

Safety Limit:

Do not exceed 5 mg/24 hours at initial prescription

Calculation Example:

If patient takes oral morphine equivalent (OME) = 600 mg/day:

IT morphine = 600 ÷ 300 = 2 mg/24 hours

Adverse Effects

Common morphine-related effects to monitor:

Nausea, vomiting
Constipation
Respiratory depression
Cardiovascular depression
Sedation or sometimes excitation
Confusion
Intracranial hypertension

Management of Overdose

Mild Symptoms:

Reduce morphine dosage by 10-30%

Frank Overdose:

Naloxone by titration
Emergency emptying of reservoir
If possible, analyze intrathecal mixture to check for preparation errors

Local Anesthetics: Neuropathic Pain Management

Ropivacaine (Preferred in France)

Classification: Long-acting local analgesic

Mechanism:

Reversible decrease in nerve fiber membrane permeability to sodium ions
Stabilization of neuron membranes
Local blockade of nerve impulses

Indications:

Intense neuropathic pain
Mixed pain syndromes with neuropathic component

Initial Dosing:

Standard range: 6-8 mg/day
Dosing according to catheter level:
- Cervical catheter: better 6 mg/24h
- Low thoracic catheter: better 8 mg/24h

Available Presentations (France):

Ropivacaine hydrochloride 10 mg/mL (200 mg in 20 mL, 150 mg in 20 mL)
Ropivacaine 7.5 mg/mL
Ropivacaine 2 mg/mL (400 mg in 200 mL)
pH of commercial solution: 5.5

Adverse Effects:

Paresthesia/hypoesthesia
Anesthesia if catheter positioned anterior or lateral
Hypotension
Motor weakness (rare if catheter correctly positioned posteriorly)

Management:

Reduce dosage by 10-30% if symptoms occur
Verify catheter positioning if motor block develops

Bupivacaine (Alternative)

Initial Dosing:

Dosing according to catheter level (similar principles to ropivacaine)

Available Presentations (France):

Bupivacaine hydrochloride 40 mg/mL (200 mg in 5 mL)
pH: 5.7

Advantages:

Higher concentration (40 mg/mL vs 10 mg/mL for ropivacaine)
Useful when large volume of ropivacaine would shorten refill intervals
Can extend time between pump fillings

Adverse Effects: Similar to ropivacaine

Ziconotide: Novel Analgesic for Neuropathic Pain

Classification and Mechanism

Type: N-type calcium channel blocker (unique mechanism)

Mechanism:

Direct inhibition of voltage-dependent calcium channels in primary nociceptive afferent nerve endings
Activation of potassium channels
Inhibition of nociceptive neurotransmitter release (including substance P)
Result: Blockage of perception of pain signals

Unique Properties:

Intrathecal route only (not effective systemically)
Non-opioid mechanism (no cross-tolerance)
Particularly effective for neuropathic pain

Indications

Intense chronic pain in adults
Strong neuropathic component
Opioid-resistant pain
Adjuvant in mixed pain syndromes

Initial Dosing

Starting dose: 0.25-0.50 µg/day

Dosing according to catheter level:

Cervical catheter: better 0.25 µg/24h
Low thoracic catheter: better 0.50 µg/24h

Titration Strategy:

According to SFETD guidelines:

Increase ziconotide very gradually to seek co-analgesic effect
Typical increase: 0.1-0.2 µg/24h at different fillings
Maximum recommended increase: 0.5 µg/24h per week
Goal: Achieve tolerance while building efficacy

Rationale: “The sooner ziconotide is introduced, the better tolerated it will be, as increases can be made very gradually.”

Available Presentations (France)

Ziconotide acetate 100 µg/mL (100 µg in 1 mL, 500 µg in 5 mL)
pH: 5.1

Adverse Effects

Neuropsychological effects to monitor:

Delirium
Dizziness
Nystagmus (involuntary eye movement)
Memory disorders
Headaches
Auditory hallucinations
Drowsiness
Blurred vision
Nausea, vomiting

Management of Adverse Effects

Clear reduction in ziconotide sometimes >50% without necessarily stopping it
Gradual withdrawal if neuropsychological symptoms are prominent
Re-titration at slower rate after stabilization

Drug Combinations and Compatibility

Approved Combinations

According to SFETD protocols, compatible intrathecal mixtures include:

Triple Therapy (Most Common):

Morphine + Ropivacaine + Ziconotide (MRZ)

Dual Therapy Options:

Morphine + Ropivacaine
Morphine + Bupivacaine (MBuZ with ziconotide)
Morphine + Ziconotide

pH Considerations

The SFETD Toolbox provides pH data for commercial solutions:

Morphine sulfate 50 mg/mL: pH = 3.4
Ropivacaine 10 mg/mL: pH = 5.5
Bupivacaine 40 mg/mL: pH = 5.7
Ziconotide 100 µg/mL: pH = 5.1

Clinical Relevance: pH affects drug stability. According to cited research, ziconotide stability in admixtures is pH-dependent:

Stability: 43.5 days if pH < 4.5
Stability: 13 days if pH ≥ 4.5

Drug Stability Data

Storage Requirements

According to SFETD pharmacy guidelines:

Syringe Storage (Polypropylene):

Morphine sulfate + Ropivacaine + Ziconotide mixture
Temperature: 2-8°C (refrigerated)
Keep in the dark to prevent plasticizer release
Stability: 3 days

SynchroMed II Pump (37°C):

Morphine monotherapy:

25 mg/mL concentration: 180 days at body temperature
Maximum concentration approved by Medtronic: 25 mg/mL

Morphine + Ropivacaine + Ziconotide:

43.5 days if pH < 4.5
13 days if pH ≥ 4.5

Practical Recommendation:

For classic morphine-ropivacaine-ziconotide mixture in SynchroMed II pump:

Maximum recommended duration: 21 days in clinical practice

This accounts for stability, safety margins, and practical refill scheduling.

Flow Rate Settings

Implanted Pumps (IDDS)

Initial Flow Rate: Start at 1 mL/day

Rationale: This round figure facilitates flow rate adjustments during initial hospitalization and titration phase.

External Pumps (Intrathecal Site)

Initial Flow Rate: Start at 4.8 mL/day (0.2 mL/hour on syringe pump)

Rationale: Provides flexibility for dose adjustments and allows accurate titration with external PCA-type pumps.

Bolus Dosing Protocols

Patient-Controlled Boluses

The SFETD Toolbox recommends offering patients the option to self-administer boluses via remote control (myPTM system) for breakthrough pain.

Key Patient Education:

Intrathecal boluses are very different from intravenous boluses:

No “shoot” effect (no immediate rush sensation)
Longer duration of action (typically effective >15 minutes)
Onset depends on bolus administration rate

Initial Bolus Parameters:

Bolus Size:

Intrathecal Site (ITS): 1/24 of daily dose (often 0.2 mL, maximum round figure)
Implanted pump (IDDS): 1/10 of daily dose

Refractory Period: 1 hour (lockout time between boluses)

Number Authorized: Often 10-12 boluses per 24 hours at first fill

Clinical Example

Patient Profile:

Mr. X with refractory pelvic and lower limb pain
Secondary lesions from prostatic adenocarcinoma
Currently on morphine sustained release 200 mg BID + 5 interdoses of 40 mg morphine immediate release
Insufficiently relieved

First Syringe Calculation:

Oral Morphine Equivalent (OME) = 600 mg/day

Morphine IT:

600 ÷ 300 = 2 mg/24 hours

Ropivacaine IT:

Low pain location, low thoracic catheter = 8 mg/24 hours

Ziconotide IT:

Low pain location, low thoracic catheter = 0.5 µg/24 hours

Flow Rate: 1 mL/day (IDDS)

Bolus: 0.1 mL (1/10 daily dose), refractory period 1 hour, 10-12 boluses authorized

Dose Adjustment Guidelines

When Analgesia is Insufficient

If Patient Uses Boluses Effectively:

Integrate boluses into base flow rate (typically increase base dosage by 30%)

If Mixed Pain (Most Common):

Increase overall treatment maintaining satisfactory morphine/local anesthetic ratio
Ideal ratio example: morphine 1 : ropivacaine 6 (e.g., 5 mg morphine : 30 mg ropivacaine)

Pain Type-Specific Adjustments:

Neuropathic predominant:

Preferentially increase local anesthetic (base dose 10-30%)
Adjust bolus to 10% of daily dose

Nociceptive predominant:

Preferentially increase morphine (base dose 10-30%)
Adjust bolus to 10% of daily dose

Mixed pain:

Increase overall treatment proportionally (base dose 10-30%)

When Analgesia is Satisfactory

Goal: Find the lowest effective dosage

Strategy:

Increase ziconotide very gradually to seek co-analgesic effect
Typical increase: 0.1-0.2 µg/24h at different fillings
Well-tolerated maintenance (max recommended increase: 0.5 µg/24h per week)
Adapt number and dose of boluses to extend filling interval

Prescription Safety

SFETD Safety Recommendations

Critical Principle: Patient safety must remain the priority.

Avoid:

Hand-written prescriptions on plain paper (source of errors and overdose risk)

Preferred:

Tools on hospital’s secure server
Shared calculator with pharmacy communication
Systems where calculations cannot easily be changed by mistake

Required Traceability:

Patient identity: last name, first name, date of birth, file number
Date of prescription
Date of filling
Prescribing doctor signature
Some facilities require two prescribing physicians to sign

Prescription Storage:

Store prescriptions to keep history and reference for subsequent prescriptions

Less Common Intrathecal Agents

The SFETD Toolbox notes that other treatments are sometimes used intrathecally:

Sufentanil (synthetic opioid)
Fentanyl (synthetic opioid)
Clonidine (alpha-2 agonist)

These are typically reserved for specific clinical scenarios or as alternatives in PACC second/third-line recommendations.

References

This educational content is synthesized from:

SFETD Intrathecal Analgesia Toolbox (2024)
Deer TR, et al. The Polyanalgesic Consensus Conference (PACC): Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating Risks. Neuromodulation. 2017 Feb;20(2):155-176.
Robert J, et al. Chemical Stability of Morphine, Ropivacaine, and Ziconotide in Combination for Intrathecal Analgesia. Int J Pharm Compd. 2017 Aug;21(4):347-351.
Bazin C, et al. Influence of pH and temperature on ziconotide stability in intrathecal analgesic admixtures. Int J Pharm. 2015 Jun;487(1-2):285-291.

For safe, structured intrathecal prescription aligned with SFETD protocols, Thalivia provides automated dose calculations and stability-aware prescription management.